Beta Amyloid Peptide: Vaccine on Beta amyloid ~ Vaccine Against Amyloid Beta ~Papers on Vaccine

Vaccine on Beta amyloid ~ Vaccine Against Amyloid Beta ~Papers on Vaccine

Vaccine on Beta amyloid ~  Vaccine Against Amyloid Beta~Beta Amyloid Papers on Vaccine

 


1.
Indian J Exp Biol. 2010 Nov;48(11):1098-102.

I32E and V36K double mutation in beta2-sheet abrogates amyloid beta peptide toxicity.

Department of Neurochemistry, National Institute of Mental Health & Neurosciences, Bangalore 560 029, India. sarada@nimhans.kar.nic.in

Abstract

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, wherein, the accumulation of amyloid beta (Abeta) peptide as cytotoxic oligomers leads to neuropathologic changes. Transgenic mice with brain Abeta plaques immunized with aggregated Abeta have reduced amyloid burden and improved cognitive functions. However, such active immunization in humans led to a small but significant occurrence of meningoencephalitis in 6% AD volunteers due to Abeta induced toxicity. In an attempt to develop safer alternative vaccines, the design of a highly soluble peptide homologous to Abeta (Abeta-EK), that has a reduced amyloidogenic potential while maintaining the major immunogenic epitopes of Abeta is reported. More importantly, this homologue has been shown to be non-toxic, as this peptide failed to exert any observable effect on erythrocytes. The results of the present study suggests that immunization with non-toxic Abeta derivative may offer a safer therapeutic approach to AD, instead of using toxic Abeta fibrils.
PMID: 21117449 [PubMed - in process]
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2.
Immunol Cell Biol. 2010 Nov 23. [Epub ahead of print]

A multimeric immunogen for the induction of immune memory to beta-amyloid.

Istituto di Genetica e Biofisica ABT, CNR, Naples, Italy.

Abstract

The development of active immunotherapy for Alzheimer's disease (AD) requires the identification of immunogens that can ensure a high titer antibody response toward beta-amyloid, whereas minimizing the risks of a cell-mediated adverse reaction. We describe here two novel anti-beta-amyloid vaccines that consist of 'virus like particles' formed by a domain of the bacterial protein E2 that is able to self-assemble into a 60-mer peptide. Peptides 1-11 and 2-6 of beta-amyloid were displayed as N terminal fusions on the surface of the E2 particles. E2-based vaccines induced a fast-rising, robust and persistent antibody response to beta-amyloid in all vaccinated mice. The immune memory induced by a single administration of vaccine (1-11) E2 can be rapidly mobilized by a single booster injection, leading to a very high serum concentration of anti-beta-amyloid antibodies (above 1 mg ml(-1)). E2 vaccination polarizes the immune response toward the production of the anti-inflammatory cytokine interleukin-4 and does not induce a T cell response to beta-amyloid. Thus, E2-based vaccines are promising candidates for the development of immunotherapy protocols for AD.Immunology and Cell Biology advance online publication, 23 November 2010; doi:10.1038/icb.2010.134.
PMID: 21102534 [PubMed - as supplied by publisher]
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3.
Immunotherapy. 2010 Nov;2(6):767-82.

Bapineuzumab: anti-β-amyloid monoclonal antibodies for the treatment of Alzheimer's disease.

Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. geriat.dot@geriatria.uniba.it

Abstract

In the last decade, new therapeutic approaches targeting β-amyloid (Aβ) have been discovered and developed with the hope of modifying the natural history of Alzheimer's disease (AD). The most revolutionary of these approaches consists in the removal of brain Aβ via anti-Aβ antibodies. After an active vaccine (AN1792) was discontinued in 2002 due to occurrence of meningoencephalitis in approximately 6% of patients, several other second-generation active Aβ vaccines and passive Aβ immunotherapies have been developed and are under clinical investigation with the aim of accelerating Aβ clearance from the brain of AD patients. The most advanced of these immunological approaches is bapineuzumab, which is composed of humanized anti-Aβ monoclonal antibodies that has been tested in two Phase II trials. Bapineuzumab has been shown to reduce Aβ burden in the brain of AD patients. However, its preliminary cognitive efficacy appears uncertain, particularly in ApoE ε4 carriers, and vasogenic edema may limit its clinical use. The results of four ongoing large Phase III trials on bapineuzumab will provide answers regarding whether passive anti-Aβ immunization is able to alter the course of this devastating disease.
PMID: 21091109 [PubMed - in process]
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4.
Hum Vaccin. 2010 Nov 1;6(11):64-68. [Epub ahead of print]

AFFITOME® technology in neurodegenerative diseases: The doubling advantage.

AFFiRiS AG,Vienna, Austria.

Abstract

Neurodegenerative diseases are still an area of unmet medical need. This is in contrast to our increasing knowledge on their pathology (e.g., Alzheimer's- (AD), Parkinson's (PD) disease). They are driven by the cerebral accumulation and aggregation of specific proteins (e.g., β-amyloid and hyperphosphorylated tau in the case of AD) in defined brain regions and, as a consequence, death of neurons. Accordingly, removal of given protein aggregates is expected to modify the course of the respective neurodegenerative disease. This has been convincingly demonstrated in animal models of human diseases. However, not every technology that can be used and proves successful in animal models can be translated to the human situation. As highlighted by recent progress in the field of AD research, specific immunotherapy is a viable option in this regard. Given the fact that the aggregates are composed of self-proteins, immunotherapeutic approaches have to consider the issue of potential autoimmunity. This is especially true in case of vaccines. An innovative solution to this problem is offered by the so called AFFITOME® technology, which relies on the use of "doubles" of native molecules, functionally mimotopes or AFFITOPES® if identified by AFFiRiS, as the antigenic vaccine component.
PMID: 20980801 [PubMed - as supplied by publisher]
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5.
Hum Vaccin. 2010 Nov 1;6(11):52-63. [Epub ahead of print]

Simplified β-amyloid peptides for safer Alzheimer's vaccines development.

Tecnogen S.p.A., Località La Fagianeria; Italy.

Abstract

Over the past few years, new ways of fighting Alzheimer's disease have emerged based on stimulating the immunitary defence system of the patients. To avoid toxicity and autoimmune response related to the Aβ[1-42] peptide immunotherapy, in the last decade a large number of works aimed at identifying new classes of safe Aβ derivatives by modifying the full length β-amyloid form. In strict agreement with the purposes of the sequence-simplification technology, Aβ[1-16], Aβ[13-28] and Aβ[25-42] fragments were selected in order to retain the major immunogenic sites of the Aβ[1-42] peptide, and corresponding simplified forms were designed and synthesized. All glycinated Aβ derivatives showed immunogenic and antigenic properties similar to the parent Aβ[1-42] peptide, and raised antibodies were all able to cross-recognize both Aβ[1-42] and Aβ[1-40] synthetic structures. All Aβ simplified forms showed reduced fibrillogenic and inflammatory properties. In particular, the Aβ[13-28]+G form failed to induce IFN-γ production thus suggesting that this molecule could represent a good candidate for potentially safer AD vaccine therapy.
PMID: 20980800 [PubMed - as supplied by publisher]
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6.
J Immunol. 2010 Nov 15;185(10):6338-47. Epub 2010 Oct 13.

Active immunization with amyloid-beta 1-42 impairs memory performance through TLR2/4-dependent activation of the innate immune system.

Neurologische Uniklinik, Technische Universität München, Munich, Germany.

Abstract

Active immunization with amyloid-β (Aβ) peptide 1-42 reverses amyloid plaque deposition in the CNS of patients with Alzheimer's disease and in amyloid precursor protein transgenic mice. However, this treatment may also cause severe, life-threatening meningoencephalitis. Physiological responses to immunization with Aβ(1-42) are poorly understood. In this study, we characterized cognitive and immunological consequences of Aβ(1-42)/CFA immunization in C57BL/6 mice. In contrast to mice immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55)/CFA or CFA alone, Aβ(1-42)/CFA immunization resulted in impaired exploratory activity, habituation learning, and spatial-learning abilities in the open field. As morphological substrate of this neurocognitive phenotype, we identified a disseminated, nonfocal immune cell infiltrate in the CNS of Aβ(1-42)/CFA-immunized animals. In contrast to MOG(35-55)/CFA and PBS/CFA controls, the majority of infiltrating cells in Aβ(1-42)/CFA-immunized mice were CD11b(+)CD14(+) and CD45(high), indicating their blood-borne monocyte/macrophage origin. Immunization with Aβ(1-42)/CFA was significantly more potent than immunization with MOG(35-55)/CFA or CFA alone in activating macrophages in the secondary lymphoid compartment and peripheral tissues. Studies with TLR2/4-deficient mice revealed that the TLR2/4 pathway mediated the Aβ(1-42)-dependent proinflammatory cytokine release from cells of the innate immune system. In line with this, TLR2/4 knockout mice were protected from cognitive impairment upon immunization with Aβ(1-42)/CFA. Thus, this study identifies adjuvant effects of Aβ(1-42), which result in a clinically relevant neurocognitive phenotype highlighting potential risks of Aβ immunotherapy.
PMID: 20943998 [PubMed - indexed for MEDLINE]
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7.
J Am Osteopath Assoc. 2010 Sep;110(9 Suppl 8):S27-36.

Investigational medications for treatment of patients with Alzheimer disease.

Department of Pharmacology, Midwestern University/Arizona College of Osteopathic Medicine, Glendale, Arizona 85308-6813, USA. ppotte@midwestern.edu

Abstract

Development of effective treatments for patients with Alzheimer disease has been challenging. Currently approved treatments include acetylcholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine hydrochloride. To investigate treatments in development for patients with Alzheimer disease, the author conducted a review of the literature. New approaches for treatment or prevention focus on several general areas, including cholinergic receptor agonists, drugs to decrease β-amyloid and tau levels, antiinflammatory agents, drugs to increase nitric oxide and cyclic guanosine monophosphate levels, and substances to reduce cell death or promote cellular regeneration. The author focuses on medications currently in clinical trials. Cholinergic agents include orthostatic and allosteric muscarinic M1 agonists and nicotinic receptor agonists. Investigational agents that target β-amyloid include vaccines, antibodies, and inhibitors of β-amyloid production. Anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs, the natural product curcumin, and the tumor necrosis factor α inhibitor etanercept, have also been studied. Some drugs currently approved for other uses may also show promise for treatment of patients with Alzheimer disease. Results of clinical trials with many of these investigational drugs have been disappointing, perhaps because of their use with patients in advanced stages of Alzheimer disease. Effective treatment may need to begin earlier-before neurodegeneration becomes severe enough for symptoms to appear.
PMID: 20926740 [PubMed - in process]
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8.
J Alzheimers Dis. 2010 Jan 1;22(4):1351-61.

Assessment of Non-Viral Amyloid-β DNA Vaccines on Amyloid-β Reduction and Safety in Rhesus Monkeys.

Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, Japan.

Abstract

We recently demonstrated that newly developed non-viral amyloid-β (Aβ) DNA vaccines are safe and effective in reducing Aβ burdens in the brains of Alzheimer's disease (AD) model mice. The present study was undertaken to examine whether DNA vaccines effectively and safely reduce Aβ deposition in the brain of rhesus monkeys. For this purpose, DNA vaccines or empty vector at a dose of 3 mg were injected intramuscularly on a biweekly basis into rhesus monkeys (15--18 years old). Before and during vaccination, blood was drawn once a month and used for hematological and biochemical examinations. Six months after the first vaccination, it was demonstrated that anti-Aβ antibodies in plasma of vaccinated monkeys were significantly elevated than that of control monkeys. Immunohistochemical examinations revealed that DNA vaccination reduced the Aβ burden to approximately 50% of that found in control monkeys (p=0.026). There was neither inflammation nor microhemorrhage in the brain and no significant changes in cytokine and chemokine levels in the blood throughout the observation period. Taken together, DNA vaccination to monkeys is safe and effective in Aβ reduction and provides useful information for performing preclinical and clinical trials.
PMID: 20930304 [PubMed - in process]
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9.
J Neuroinflammation. 2010 Sep 28;7:57.

Therapeutic versus neuroinflammatory effects of passive immunization is dependent on Aβ/amyloid burden in a transgenic mouse model of Alzheimer's disease.

Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20057, USA.

Abstract

BACKGROUND: Passive immunization with antibodies directed to Aβ decreases brain Aβ/amyloid burden and preserves memory in transgenic mouse models of Alzheimer's disease (AD). This therapeutic strategy is under intense scrutiny in clinical studies, but its application is limited by neuroinflammatory side effects (autoimmune encephalitis and vasogenic edema).
METHODS: We intravenously administered the monoclonal Aβ protofibril antibody PFA1 to aged (22 month) male and female 3 × tg AD mice with intermediate or advanced AD-like neuropathologies, respectively, and measured brain and serum Aβ and CNS cytokine levels. We also examined 17 month old 3 × tg AD female mice with intermediate pathology to determine the effect of amyloid burden on responses to passive immunization.
RESULTS: The 22 month old male mice immunized with PFA1 had decreased brain Aβ, increased serum Aβ, and no change in CNS cytokine levels. In contrast, 22 month old immunized female mice revealed no change in brain Aβ, decreased serum Aβ, and increased CNS cytokine levels. Identical experiments in younger (17 month old) female 3 × tg AD mice with intermediate AD-like neuropathologies revealed a trend towards decreased brain Aβ and increased serum Aβ accompanied by a decrease in CNS MCP-1.
CONCLUSIONS: These data suggest that passive immunization with PFA1 in 3 × tg AD mice with intermediate disease burden, regardless of sex, is effective in mediating potentially therapeutic effects such as lowering brain Aβ. In contrast, passive immunization of mice with a more advanced amyloid burden may result in potentially adverse effects (encephalitis and vasogenic edema) mediated by certain proinflammatory cytokines.
PMID: 20920207 [PubMed - indexed for MEDLINE]PMCID: PMC2955708Free PMC Article
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10.
Hum Vaccin. 2010 Nov 9;6(11). [Epub ahead of print]

Virus-like particle based vaccines for Alzheimer disease.

Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA. bchackerian@salud.unm.edu.

Abstract

Vaccines targeting the amyloid-β (Aβ) peptide have promise as immunotherapies for the treatment of Alzheimer disease (AD). Human trials of a first generation Aβ vaccine highlighted the need for a vaccine strategy that could consistently induce high-titer antibodies against Aβ without also inducing inflammatory auto-reactive T cell responses. In this review, I will describe the use of virus-like particle (VLP) based vaccines against Aβ that can potentially satisfy these demands. VLPs can serve as highly multivalent platforms for the display of diverse antigens on their surfaces. VLP display markedly increases the immunogenicity of antigens, including self-antigens. VLP-based immunogens targeting Ab have been developed by several different groups, and have demonstrated effectiveness in animal models of AD. One VLP-based candidate vaccine for AD, CAD106, developed by Cytos Biotechnology and Novartis Pharmaceuticals, is currently in human clinical trials.
PMID: 20864801 [PubMed - as supplied by publisher]
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11.
J Neuroimmunol. 2010 Dec 15;229(1-2):248-55. Epub 2010 Sep 22.

Anti-11[E]-pyroglutamate-modified amyloid β antibodies cross-react with other pathological Aβ species: relevance for immunotherapy.

Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Cuidad Universitaria, México DF, Mexico.

Abstract

N-truncated/modified forms of amyloid beta (Aß) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as well as animal models of AD, and represent highly desirable therapeutic targets. In the present study we have focused on N-truncated/modified Aβ peptide bearing amino-terminal pyroglutamate at position 11 (AβN11(pE)). We identified two B-cell epitopes recognized by rabbit anti-AβN11(pE) polyclonal antibodies. Interestingly, rabbit anti-AβN11(pE) polyclonal antibodies bound also to full-length Aβ1-42 and N-truncated/modified AβN3(pE), suggesting that the three peptides may share a common B-cell epitope. Importantly, rabbit anti-AβN11(pE) antibodies bound to naturally occurring Aβ aggregates present in brain samples from AD patients. These results are potentially important for developing novel immunogens for targeting N-truncated/modified Aβ aggregates as well, since the most commonly used immunogens in the majority of vaccine studies have been shown to induce antibodies that recognize the N-terminal immunodominant epitope (EFRH) of the full length Aβ, which is absent in N-amino truncated peptides.
Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20864186 [PubMed - indexed for MEDLINE]PMCID: PMC2991418 [Available on 2011/12/1]
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12.

[Immunotherapy and Alzheimer's disease].

[Article in Japanese]
Department of Psychiatry, Juntendo University Faculty of Medicine, Tokyo, Japan. heii@juntendo.ac.jp

Abstract

Recent progress in biological studies on Alzheimer's disease (AD) could lead to a new strategy for its treatment. One of the representative and leading therapies is passive and active immunotherapy. The first active immunotherapy using the full length of Abeta protein was stopped due to the serious side-effect of encephalitis. Currently, a new revised immunotherapy using humanized mouse monoclonal antiserum against a part of Abeta protein is under clinical trials. Here, future advance concerning AD treatment as well as the present situation will be reviewed.
PMID: 20857695 [PubMed - indexed for MEDLINE]
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14.
J Alzheimers Dis. 2010 Aug 6. [Epub ahead of print]

Modified Immunotherapies Against Alzheimer's Disease: Toward Safer and Effective Amyloid-beta Clearance.

Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.

Abstract

Alzheimer's disease (AD) is characterized by the deposition of amyloid plaques, loss of neurons, neuritic degeneration, accumulation of fibrillary tangles in neurons, and a progressive loss of cognitive function. Amyloid-beta peptide (Abeta) appears to play a pivotal role in the development of AD. Clearance of Abeta from the brain represents an important therapeutic strategy for prevention and treatment of AD. Immunotherapy targeting Abeta is effective to remove the peptide from the brain. However, it is associated with detrimental adverse effects, such as autoimmune meningoencephalitis and microhemorrhage. These are presumably the result of brain infiltration of provoked autoimmune T lymphocytes in response to Abeta vaccination and release of proinflammatory cytokines from microglia activated by the immune complex of Abeta and antibodies. An improvement of the safety of the immunotherapy is a major goal of the immunotherapy study. Here, we review the mechanisms involved in modified immunological strategies, as well as their adverse effects. We discuss the following: the development of B epitope vaccines to avoid activation of autoimmune T lymphocytes; DNA vaccines containing appropriate immunostimulatory and immunomodulatory sequences to induce the desired humoral immune responses; antibody modifications to avoid activation of microglia and subsequent release of proinflammatory cytokines; single chain antibody-based gene therapy; immunotherapy targeting Abeta oligomers; modulation of antibody delivery approach and dose; and application of autoantibodies against Abeta. These ultimately represent future directions of therapeutic approaches toward safer and effective Abeta clearance.
PMID: 20693643 [PubMed - as supplied by publisher]
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15.
J Virol Methods. 2010 Nov;169(2):332-40. Epub 2010 Aug 5.

Cucumber mosaic virus as the expression system for a potential vaccine against Alzheimer's disease.

Department of Biology, Plant Protection and Agrobiotechnology, University of Basilicata, Viale dell'Ateneo Lucano, 10, 85100 Potenza, Italy.

Abstract

A primary therapeutic goal in Alzheimer's disease (AD) is to reduce the quantity of amyloid β protein (Aβ) present in the brain. To develop an effective, safe system for vaccination against Alzheimer's disease, the plant virus Cucumber mosaic virus (CMV) was engineered genetically to express Aβ-derived fragments that stimulate mainly humoral immune responses. Six chimeric constructs, bearing the Aβ1-15 or the Aβ4-15 sequence in positions 248, 392 or 529 of the CMV coat protein (CP) gene, were created. Viral products proved to be able to replicate in their natural host. However, only chimeric Aβ1-15-CMVs were detected by Aβ1-42 antiserum in Western blot analysis. Experimental evidence of Immunoelectron microscopy revealed a complete decoration of Aβ1-15-CMV(248) and Aβ1-15-CMV(392) following incubation with either anti-Aβ1-15 or anti-Aβ1-42 polyclonal antibodies. These two chimeric CMVs appear to be endowed with features making them possible candidates for vaccination against Alzheimer's disease.
Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20691733 [PubMed - indexed for MEDLINE]
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16.
Biochem Biophys Res Commun. 2010 Sep 3;399(4):593-9. Epub 2010 Aug 1.

Reduction of amyloid beta-peptide accumulation in Tg2576 transgenic mice by oral vaccination.

Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Japan.

Abstract

Alzheimer's disease (AD) is pathologically characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles. Amyloid beta-peptide (Abeta) is the main component of senile plaques, and the pathological load of Abeta in the brain has been shown to be a marker of the severity of AD. Abeta is produced from the amyloid precursor protein by membrane proteases and is known to aggregate. Recently, immune-mediated cerebral clearance of Abeta has been studied extensively as potential therapeutic strategy. In previous studies that used a purified Abeta challenge in a mouse model of AD, symptomatic improvement was reported. However, a clinical Alzheimer's vaccine trial in the United States was stopped because of severe side effects. Immunization with the strong adjuvant used in these trials might have activated an inflammatory Th1 response. In this study, to establish a novel, safer, lower-cost therapy for AD, we tested an oral vaccination in a wild-type and a transgenic mouse model of AD administered via green pepper leaves expressing GFP-Abeta. Anti-Abeta antibodies were effectively induced after oral immunization. We examined the immunological effects in detail and identified no inflammatory reactions. Furthermore, we demonstrated a reduction of Abeta in the immunized AD-model mice. These results suggest this edible vehicle for Abeta vaccination has a potential clinical application in the treatment of AD.
Copyright 2010 Elsevier Inc. All rights reserved.
PMID: 20682291 [PubMed - indexed for MEDLINE]
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17.
Brain Nerve. 2010 Jul;62(7):659-66.

[Treatment strategy of Alzheimer's disease: pause in clinical trials of Abeta vaccine and next steps].

[Article in Japanese]
Department of Medical Welfare, Faculty of Health Science, Suzuka University of Medical Science, Suzuka, Mie, Japan.

Abstract

The important pathognomonic features of Alzheimer disease (AD) brain are the occurrence of abundant neurofibrillary tangles (NFTs) in neurons and presence of extracellular deposits of beta-amyloid (Abeta)- senile plaques. In the early 1980s, the NFTs were characterized, and cerebral amyloid was purified; further the amino acid sequences of the tau protein in the NFTs and of Abeta were identified. Immunohistochemical studies with antibodies to tau and Abeta revealed that extracellular accumulation of Abeta precedes that of tau in neurons. Molecular genetic studies revealed that abnormal gene mutations of familial AD accelerate Abeta production. On the basis of these findings, the amyloid cascade hypothesis that Abeta accumulation is the primary cause of neuronal degeneration and induces accumulation of tau in the AD brain was proposed and widely accepted. Thus, on the basis of this hypothesis, transgenic AD mice were treated with Abeta vaccine; the Abeta amyloid plaques were eliminated, and a dramatic improvement of the behavioral deficits was observed in the treated mice. The great success of preclinical studies promoted clinical trials of the Abeta vaccine in AD patients. However,the clinical trials were discontinued because of the occurrence of severe meningoencephalitis. Postmortem examination of the brains of the vaccinated patients with high titer of the anti- Abeta antibody in the serum revealed elimination of the Abeta plaques along with presence of cerebral inflammation. However, in autopsy-proven cases, assessment of the clinical and cognitive functions of the patients did not provide any evidence for improved survival or prolongation of the time to severe dementia. Thus, anti-Abeta antibody could eliminate the accumulated Abeta but could not rescue the degenerated neurons. Thus, the AD treatment strategy should be converted from repair and cure of AD to prevention. Anti-Abeta therapy must be started at the preclinical stage, and it is necessary to focus on tau and other proteins, mitochondria, glial cells, and other factors that influence the degeneration of neurons.
PMID: 20675870 [PubMed - indexed for MEDLINE]
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18.
Acta Neuropathol. 2010 Sep;120(3):369-84. Epub 2010 Jul 15.

Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer's disease pathogenesis.

Division of Clinical Neurosciences, School of Medicine, Southampton General Hospital, University of Southampton, Southampton SO16 6YD, UK. d.boche@soton.ac.uk

Abstract

The amyloid cascade hypothesis of Alzheimer's disease (AD) is testable: it implies that interference with Abeta aggregation and plaque formation may be therapeutically useful. Abeta42 immunisation of amyloid precursor protein (APP) transgenic mice prevented plaque formation and caused removal of existing plaques. The first clinical studies of Abeta immunisation in AD patients (AN1792, Elan Pharmaceuticals) were halted when some patients suffered side effects. Since our confirmation that Abeta immunisation can prompt plaque removal in human AD, we have performed a clinical and neuropathological follow up of AD patients in the initial Elan Abeta immunisation trial. In immunised AD patients, we found: a lower Abeta load, with evidence that plaques had been removed; a reduced tau load in neuronal processes, but not in cell bodies; and no evidence of a beneficial effect on synapses. There were pathological "side effects" including: increased microglial activation; increased cerebral amyloid angiopathy; and there is some evidence for increased soluble/oligomeric Abeta. A pathophysiological mechanism involving effects on the cerebral vasculature is proposed for the clinical side effects observed with some active and passive vaccine protocols. Our current knowledge of the effects of Abeta immunotherapy is based on functional information from the early clinical trials and a few post mortem cases. Several further clinical studies are underway using a variety of protocols and important clinical, imaging and neuropathological data will become available in the near future. The information obtained will be important in helping to understand the pathogenesis not only of AD but also of other neurodegenerative disorders associated with protein aggregation.
PMID: 20632020 [PubMed - indexed for MEDLINE]
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20.
Biochim Biophys Acta. 2010 Oct;1804(10):2025-35. Epub 2010 Jul 7.

An Aß concatemer with altered aggregation propensities.

Interdisciplinary Nanoscience Centre (iNANO), Center for insoluble Protein Structures (inSPIN), Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.

Abstract

We present an analysis of the conformational and aggregative properties of an Aß concatemer (Con-Alz) of interest for vaccine development against Alzheimer's disease. Con-Alz consists of 3 copies of the 43 residues of the Aß peptide separated by the P2 and P30 T-cell epitopes from the tetanus toxin. Even in the presence of high concentrations of denaturants or fluorinated alcohols, Con-Alz has a very high propensity to form aggregates which slowly coalesce over time with changes in secondary, tertiary and quaternary structure. Only micellar concentrations of SDS were able to inhibit aggregation. The increase in the ability to bind the fibril-binding dye ThT increases without lag time, which is characteristic of relatively amorphous aggregates. Confirming this, electron microscopy reveals that Con-Alz adopts a morphology resembling truncated protofibrils after prolonged incubation, but it is unable to assemble into classical amyloid fibrils. Despite its high propensity to aggregate, Con-Alz does not show any significant ability to permeabilize vesicles, which for fibrillating proteins is taken to be a key factor in aggregate cytotoxicity and is attributed to oligomers formed at an early stage in the fibrillation process. Physically linking multiple copies of the Aß-peptide may thus sterically restrict Con-Alz against forming cytotoxic oligomers, forcing it instead to adopt a less well-organized assembly of intermeshed polypeptide chains.
Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20619363 [PubMed - indexed for MEDLINE]
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21.
Curr Med Chem. 2010;17(25):2764-74.

New therapeutic strategy for Parkinson's and Alzheimer's disease.

IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.

Abstract

The development of potential neuroprotective therapies for neurodegenerative diseases (Parkinson's and Alzheimer's Disease) must be based on understanding their molecular and biochemical pathogenesis. Many potential pathways of neuronal cell death have been implicated in a mouse model of neurodegenerative disease, including excitotoxicity, toxicity from reactive oxygen species (superoxide anion, nitric oxide, hydroxyl radical), apoptosis (caspase-dependent and -independent pathways), necrosis and glial injury. Some agents that act on these pathways may be available for protecting the brain against chronic neurodegenerative conditions like Parkinson's and Alzheimer's disease. Drugs currently used to treat neurological disease and injuries provide temporary relief of symptoms but do not stop or slow the underlying neurodegenerative process. Restorative therapies for Parkinson's Disease are currently focused on cell replacement and administration of growth factors and small-molecule neurotrophic agents. The new experimental drugs, by contrast, target the common, underlying cause of destructive process of brain cell death. For example, p53 inhibitors attack a key protein involved in nerve cell death and represent a new strategy for preserving brain function following sudden injury or chronic disease. Analogues of pifithrin-alpha (PFT), which was shown in previous studies to inhibit p53, were designed, synthesized and tested to see whether they would work against cultured brain cells and animal models of neurodegenerative disease. Moreover, several agents based on the predominant anti-amyloid strategy, targeting amyloid-beta (Aβ) peptide, which aggregates in the plaques that are a hallmark of Alzheimer's disease, would affect disease progression. Researchers are already making great strides in developing a vaccine for this progressive brain disorder. Immunization could offer a way to blunt or even prevent the deadly, memory-robbing disease. Here we review many of potential neuroprotective therapies, and strategies that might be suited to the development of innovative approaches that prevent degeneration and restore function in Parkinson's disease.
PMID: 20586718 [PubMed - in process]
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22.
Clin Neuropathol. 2010 Jul-Aug;29(4):209-16.

Cerebral amyloid angiopathy and microhemorrhages after amyloid beta vaccination: case report and brief review.

Service d'Anatomie Pathologique, CHU Rangueil and Faculté de Médecine Rangueil, France.

Abstract

After the interruption of the international multicenter Phase 2 clinical trial with active immunotherapy based on synthetic Abeta42 (AN1792), few reports about the neuropathological findings in those patients and those from the Phase 1 clinical trial were published. These reports described some pathological similarities among the patients such as a reduction in the burden of amyloid plaques, the reactions of microglia/macrophages and the persistence of neurofibrillary tangles and neuropil threads. In addition, a lymphocytic inflammatory infiltrate as well as white matter lesions were present in some cases with meningoencephalitis. In both animal models of vaccination, as well as some vaccinated patient samples, there appears to be a correlation between vaccination and hemorrhages. Subsequently, two series reports concerning 8 patients from the Phase 1 initial trial showed that immunization with Abeta42 seemed to result in clearance of amyloid plaques, but did not prevent progressive neurodegeneration and that it increased vessel wall amyloid angiopathy as well as cortical microhemorrhages. Recent clinical data gave further encouraging results regarding vaccination in humans demonstrating that long term follow-up of patients from the second clinical trial revealed reduced functional decline, at least, in antibody responders. Here we describe a patient diagnosed with Alzheimer's disease who also participated in the Phase 2 clinical trial. A neuropathological examination confirmed Alzheimer's disease without meningoencephalitis and revealed a severe amyloid angiopathy with frequent microhemorrhages, the decrease of amyloid load being difficult to ascertain. Our results are in agreement with previous studies and confirm the presence of severe amyloid angiopathy after vaccination. The latter may be a transient phenomenon depending on the degree of immune response and the pathological stage of the disease when the patient underwent treatment. In addition, our vaccinated case also demonstrated microhemorrhages and microinfarcts which were already noticed to occur with a higher density in immunized Alzheimer's disease patients.
PMID: 20569670 [PubMed - indexed for MEDLINE]
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23.
Mol Biosyst. 2010 Oct 1;6(10):1760-6. Epub 2010 Jun 21.

Plasma beta-amyloid as potential biomarker of Alzheimer disease: possibility of diagnostic tool for Alzheimer disease.

Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Yamada-oka, Suita, Osaka 565-0871, Japan.

Abstract

Alzheimer disease (AD), which is characterized by progressive cognitive and behavioral deficit, is the most common form of dementia. The incidence of AD is increasing at an alarming rate, and has become a major public health concern in many countries. It is well known that the onset of AD is preceded by a long preclinical period. It is thus critical to establish diagnostic biomarkers that can predict the risk of developing AD prior to clinical manifestation of dementia, for effective prevention and early intervention. With the emergence of potential promising approaches to treat AD targeting the beta-amyloid (Abeta) pathway, such as gamma-secretase inhibitors and vaccine therapy, there is an urgent need for such diagnostic markers. Although cerebrospinal fluid (CSF) Abeta and tau protein levels are candidate biomarkers for AD, the invasive sampling procedure with associated complications limits their use in routine clinical practice. Plasma Abeta has been suggested as an inexpensive and non-invasive biomarker for AD. Although most previous cross-sectional studies on plasma Abeta level in humans failed to show a significant difference between individuals with AD compared to healthy older adults, many strategies are under investigation to improve the diagnostic potential of plasma Abeta. One promising approach is to modify the plasma Abeta level using some potential modulators. It is possible that a difference in plasma Abeta level might be unmasked by evaluating the response to stimulation by a modulator. Anti-Abeta antibody and Abeta binding proteins have been reported to be such modulators of plasma Abeta. In addition, the glucometabolic or hormonal status appears to modulate the plasma Abeta level. Our recent study has shown the possibility that glucose loading could be a novel simple strategy to modulate the plasma Abeta level, making it better suited for early diagnosis. This review summarizes the utility and limitations of current biomarkers of AD and discusses future strategies to improve the diagnostic potential of plasma Abeta.
PMID: 20567751 [PubMed - in process]
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24.
Vaccine. 2010 Jul 19;28(32):5280-7. Epub 2010 Jun 4.

Analysis of three plasmid systems for use in DNA A beta 42 immunization as therapy for Alzheimer's disease.

Alzheimer's Disease Center, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9036, USA.

Abstract

In an effort to optimize DNA immunization-elicited antibody production responses against A beta 1-42 (A beta 42) as a therapy for Alzheimer's disease (AD), comparisons were made between three distinct plasmid systems using gene gun delivery. Plasmids encoding A beta 42 monomer and a novel A beta 42 trimeric fusion protein were evaluated in conjunction with CMV or Gal4/UAS promoter elements. It was found that vaccination A beta 42 trimer under the Gal4/UAS promoter elicited high levels of anti-A beta 42 antibody production. Serum antibody levels from Gal4/UAS-A beta 42 trimer immunized mice were found to be 16.6+/-5.5 microg/ml compared to 6.5+/-2.5 microg/ml with Gal4/UAS-A beta 42 monomer or even less with CMV-A beta 42 trimer. As compared to monomeric A beta 42 or A beta 42 trimer expressed under the CMV promoter, injection of the Gal4/UAS-A beta 42 trimer induced high levels of A beta 42 antigen expression in tissue suggesting a mechanism for the increase in anti-A beta 42 antibody. Antibodies were found to be primarily IgG1 suggesting a predominant Th2 response (IgG1/IgG2a ratio of 9). Serum from A beta 42 trimer-vaccinated mice was also found to identify amyloid plaques in the brains of APP/PS1 transgenic mice. These results demonstrate the potential therapeutic use of Gal4/UAS DNA A beta 42 trimer immunization in preventing Alzheimer's disease.
(c) 2010 Elsevier Ltd. All rights reserved.
PMID: 20562015 [PubMed - indexed for MEDLINE]PMCID: PMC2926979 [Available on 2011/7/1]
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25.
Biochemistry. 2010 Jul 20;49(28):5899-908.

Inhibition by flavonoids of amyloid-like fibril formation by Plasmodium falciparum merozoite surface protein 2.

The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.

Abstract

Merozoite surface protein 2 (MSP2) is a glycosylphosphatidylinositol (GPI)-anchored protein expressed abundantly on the surface of Plasmodium falciparum merozoites. The results of a phase 2 trial in Papua New Guinean children showed MSP2 to be a promising malaria vaccine candidate. MSP2 is intrinsically unstructured and forms amyloid-like fibrils under physiological conditions. Oligomers containing beta-strand interactions similar to those in amyloid fibrils may be a component of the fibrillar surface coat on P. falciparum merozoites. As the propensity of MSP2 to form fibrils in solution also has the potential to impede its development as a vaccine candidate, finding an inhibitor that specifically inhibits fibrillogenesis may enhance vaccine development. In this study, we tested the ability of three flavonoids, EGCG, baicalein, and resveratrol, to inhibit MSP2 fibrillogenesis and found marked inhibition with EGCG but not with the other two flavonoids. The inhibitory effect and the interactions of the flavonoids with MSP2 were characterized using NMR spectroscopy, thioflavin T fluorescence assays, electron microscopy, and other biophysical methods. EGCG stabilizes soluble oligomers and blocks fibrillogenesis by preventing the conformational transition of MSP2 from a random coil to an amyloidogenic beta-sheet structure. Structural comparison of the three flavonoids indicates an association between their propensity for autoxidation and their fibril inhibitory activity; the activity of EGCG can be attributed to the vicinal hydroxyl groups present in this flavonoid and their ability to form quinones. The molecular mechanism of fibril inhibition by EGCG appears to be complex and involves noncovalent binding followed by covalent modification of the protein. Although the addition of EGCG appears to be an effective means of stabilizing MSP2 in solution, the covalent modification of MSP2 would most likely not be acceptable in a vaccine formulation. However, these small molecule inhibitors of MSP2 fibril formation will be useful as mechanistic probes in studying oligomerization and fibril assembly of MSP2.
PMID: 20545323 [PubMed - indexed for MEDLINE]
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26.
Hum Gene Ther. 2010 Nov;21(11):1569-76.

Low concentrations of anti-Aβ antibodies generated in Tg2576 mice by DNA epitope vaccine fused with 3C3d molecular adjuvant do not affect AD pathology.

Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA 92647, USA.

Abstract

It has been demonstrated that an active vaccination strategy with protein- or DNA-based epitope vaccines composed of the immunodominant self B cell epitope of amyloid-β₄₂ (Aβ₄₂) and a non-self T helper (Th) cell epitope is an immunotherapeutic approach to preventing or treating Alzheimer's disease (AD). As a DNA-based epitope vaccine, we used a plasmid encoding three copies of Aβ(1-11) and Th cell epitope, PADRE (p3Aβ(1-11)-PADRE). We have previously reported that three copies of component of complement C3d (3C3d) acts as a molecular adjuvant significantly enhancing immune responses in wild-type mice of the H2(b) haplotype immunized with p3Aβ(1-11)-PADRE. Here, we tested the efficacy of p3Aβ(1-11)-PADRE and the same vaccine fused with 3C3d (p3Aβ(1-11)-PADRE-3C3d) in a transgenic (Tg) mouse model of AD (Tg2576) of the H2(bxs) immune haplotype. The overall responses to both vaccines were very weak in Tg2576 mice despite the fact that the 3C3d molecular adjuvant significantly enhanced the anti-Aβ response to 3Aβ(1-11)-PADRE. Importantly, generation of low antibody responses was associated with the strain of amyloid precursor protein Tg mice rather than with a molecular adjuvant, as a p3Aβ(1-11)-PADRE-3C3d vaccine induced significantly higher antibody production in another AD mouse model, 3xTg-AD of the H2(b) haplotype. Finally, this study demonstrated that low concentrations of antibodies generated by both DNA vaccines were not sufficient for the reduction of Aβ pathology in the brains of vaccinated Tg2576 animals, confirming previous reports from preclinical studies and the AN-1792 clinical trials, which concluded that the concentration of anti-Aβ antibodies may be essential for the reduction of AD pathology.
PMID: 20528468 [PubMed - in process]PMCID: PMC2978548 [Available on 2011/11/1]
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27.
Expert Opin Biol Ther. 2010 Jul;10(7):1121-30.

Bapineuzumab.

Stanford University School of Medicine, Stanford Center for Memory Disorders, 300 Pasteur Drive, Room A343, Stanford, CA 94305-5235, USA.

Abstract

IMPORTANCE OF THE FIELD: Alzheimer's disease is the leading cause of dementia in the elderly, and there is no disease-modifying therapy yet available. Immunotherapy directed against the beta-amyloid peptide may be capable of slowing the rate of disease progression. Bapineuzumab, an anti-beta-amyloid monoclonal antibody, will be the first such agent to emerge from Phase III clinical trials.
AREAS COVERED IN THIS REVIEW: The primary literature on bapineuzumab from 2009 and 2010 is reviewed in its entirety, along with the literature on AN1792, a first-generation anti-beta-amyloid vaccine, from 2003 to 2009. Other Alzheimer's disease immunotherapeutics currently in development, according to www.clinicaltrials.gov , are also discussed.
WHAT THE READER WILL GAIN: In addition to a critical appraisal of the Phase II trial results for bapineuzumab, this review considers the broader field of immunotherapy for Alzheimer's disease as a whole, including the challenges ahead.
TAKE HOME MESSAGE: Bapineuzumab appears capable of reducing the cerebral beta-amyloid peptide burden in patients with Alzheimer's disease. However, particularly in APOE 4 carriers, its ability to slow disease progression remains uncertain, and vasogenic edema - a dose-limiting and potentially severe adverse reaction - may limit its clinical applicability.
PMID: 20497044 [PubMed - indexed for MEDLINE]PMCID: PMC3000430 [Available on 2011/7/1]
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28.
Neurobiol Dis. 2010 Sep;39(3):409-22. Epub 2010 May 20.

Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer's disease.

Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH 43205, USA.

Abstract

Vaccination has become an important therapeutic approach to the treatment of Alzheimer's disease (AD), however, immunization with Abeta amyloid can have unwanted, potentially lethal, side effects. Here we demonstrate an alternative peptide-mimotope vaccine strategy using the SDPM1 peptide. SDPM1 is a 20 amino acid peptide bounded by cysteines that binds tetramer forms of Abeta(1-40)- and Abeta(1-42)-amyloids and blocks subsequent Abeta amyloid aggregation. Immunization of mice with SDPM1 induced peptide-mimotope antibodies with the same biological activity as the SDPM1 peptide. When done prior to the onset of amyloid plaque formation, SDPM1 vaccination of APPswePSEN1(A246E) transgenic mice reduced amyloid plaque burden and Abeta(1-40) and Abeta(1-42) levels in the brain, improved cognitive performance in Morris water maze tests, and resulted in no increased T cell responses to immunogenic or Abeta peptides or brain inflammation. When done after plaque burden was already significant, SDPM1 immunization still significantly reduced amyloid plaque burden and Abeta(1-40/1-42) peptide levels in APPswePSEN1(A246E) brain without inducing encephalitogenic T cell responses or brain inflammation, but treatment at this stage did not improve cognitive function. These experiments demonstrate the efficacy of a novel vaccine approach for Alzheimer's disease where immunization with an Abeta(1-40/1-42) amyloid-specific binding and blocking peptide is used to inhibit the development of neuropathology and cognitive dysfunction.
PMID: 20493257 [PubMed - indexed for MEDLINE]PMCID: PMC2913404 [Available on 2011/9/1]
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29.
Biochim Biophys Acta. 2010 Oct;1802(10):847-59. Epub 2010 May 13.

Murine models of Alzheimer's disease and their use in developing immunotherapies.

Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. thomas.wisniewski@nyumc.org

Abstract

Alzheimer's disease (AD) is one of the categories of neurodegenerative diseases characterized by a conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it resistant to degradation and neurotoxic. In AD, the normal soluble amyloid beta (sAbeta) peptide is converted into oligomeric/fibrillar Abeta. The oligomeric forms of Abeta are thought to be the most toxic, while fibrillar Abeta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. An additional important feature of AD is the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror specific aspects of AD pathology. None of the current murine models is a perfect match of the human disease. Perhaps the most exciting of the therapeutic approaches being developed is immunomodulation targeting the aggregating proteins, Abeta and tau. This type of AD therapy is currently being assessed in many transgenic mouse models, and promising findings have led to clinical trials. However, there is a discrepancy between results in murine models and ongoing clinical trials, which highlight the limitations of these models and also of our understanding of the underlying etiology and pathogenesis of AD. Because of these uncertainties, Tg models for AD are continuously being refined with the aim to better understand the disease and to enhance the predictive validity of potential treatments such as immunotherapies.
Copyright © 2010 Elsevier B.V. All rights reserved.
PMID: 20471477 [PubMed - indexed for MEDLINE]PMCID: PMC2930136Free PMC Article
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30.
PLoS Pathog. 2010 May 6;6(5):e1000893.

Elevation of intact and proteolytic fragments of acute phase proteins constitutes the earliest systemic antiviral response in HIV-1 infection.

Henry Wellcome Building for Molecular Physiology, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, Oxfordshire, United Kingdom.

Abstract

The earliest immune responses activated in acute human immunodeficiency virus type 1 infection (AHI) exert a critical influence on subsequent virus spread or containment. During this time frame, components of the innate immune system such as macrophages and DCs, NK cells, beta-defensins, complement and other anti-microbial factors, which have all been implicated in modulating HIV infection, may play particularly important roles. A proteomics-based screen was performed on a cohort from whom samples were available at time points prior to the earliest positive HIV detection. The ability of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1 replication was analyzed using in vitro PBMC and DC infection models. Analysis of unique plasma donor panels spanning the eclipse and viral expansion phases revealed very early alterations in plasma proteins in AHI. Induction of acute phase protein serum amyloid A (A-SAA) occurred as early as 5-7 days prior to the first detection of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels. Furthermore, a proteolytic fragment of alpha-1-antitrypsin (AAT), termed virus inhibitory peptide (VIRIP), was observed in plasma coincident with viremia. Both A-SAA and VIRIP have anti-viral activity in vitro and quantitation of their plasma levels indicated that circulating concentrations are likely to be within the range of their inhibitory activity. Our results provide evidence for a first wave of host anti-viral defense occurring in the eclipse phase of AHI prior to systemic activation of other immune responses. Insights gained into the mechanism of action of acute-phase reactants and other innate molecules against HIV and how they are induced could be exploited for the future development of more efficient prophylactic vaccine strategies.
PMID: 20463814 [PubMed - indexed for MEDLINE]PMCID: PMC2865525Free PMC Article
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31.
Neurobiol Dis. 2010 Sep;39(3):301-10. Epub 2010 May 6.

Linear and conformation specific antibodies in aged beagles after prolonged vaccination with aggregated Abeta.

The Institute for Memory Impairments and Neurological Disorders, University of California, Irvine 92697-4540, USA. vvasilev@uci.edu

Abstract

Previously we showed that anti-Abeta peptide immunotherapy significantly attenuated Alzheimer's-like amyloid deposition in the central nervous system of aged canines. In this report we have characterized the changes that occurred in the humoral immune response over 2.4years in canines immunized repeatedly with aggregated Abeta(1-42) (AN1792) formulated in alum adjuvant. We observed a rapid and robust induction of anti-Abeta antibody titers, which were associated with an anti-inflammatory T helper type 2 (Th2) response. The initial antibody response was against dominant linear epitope at the N-terminus region of the Abeta(1-42) peptide, which is identical to the one in humans and vervet monkeys. After multiple immunizations the antibody response drifted toward the elevation of antibodies that recognized conformational epitopes of assembled forms of Abeta and other types of amyloid. Our findings indicate that prolonged immunization results in distinctive temporal changes in antibody profiles, which may be important for other experimental and clinical settings.
PMID: 20451612 [PubMed - indexed for MEDLINE]PMCID: PMC2910127 [Available on 2011/9/1]
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32.
Rejuvenation Res. 2010 Apr-Jun;13(2-3):179-87.

Beneficial catalytic immunity to abeta peptide.

Chemical Immunology Research Center, University of Texas-Houston Medical School, Houston, Texas 77030, USA. sudhir.paul@uth.tmc.edu

Abstract

We review attempts to treat Alzheimer disease with antibodies that bind amyloid beta peptide (Abeta) and the feasibility of developing catalytic antibodies for this purpose. Naturally occurring immunoglobulin M (IgM) class antibodies that hydrolyze Abeta and inhibit Abeta aggregation were identified. The production of these antibodies increases as a function of age, ostensibly reflecting an attempt by the immune system to protect against the deleterious effect of Abeta accumulation in old age. A search for catalytic antibodies in a library of human immunoglobulins variable (IgV) domains yielded catalysts that hydrolyzed Abeta specifically at exceptionally rapid rates. The catalytic IgVs contained the light-chain variable domains within scaffolds that are structurally reminiscent of phylogenetically ancient antibodies. Inclusion of the heavy-chain variable domain in the IgV constructs resulted in reduced catalysis. We present our view that catalytic antibodies are likely to emerge as more efficacious and safer immunotherapy reagents compared to traditional Abeta-binding antibodies.
PMID: 20370602 [PubMed - indexed for MEDLINE]PMCID: PMC2946056 [Available on 2011/4/1]
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33.
Drugs. 2010 Mar 26;70(5):513-28. doi: 10.2165/11533070-000000000-00000.

Intravenous immunoglobulins as a treatment for Alzheimer's disease: rationale and current evidence.

Department of Neurology, Philipps-University, Marburg, Germany. dodel@med.uni-marburg.de

Abstract

Current treatment options for Alzheimer's disease (AD) exert only a short-lived effect on disease symptoms. Active and passive immunotherapy have both been shown to be effective in clearing plaques, removing beta-amyloid (Abeta) and improving behaviour in animal models of AD. Although the first active immunization trial in humans was discontinued because of severe adverse effects, several new approaches are currently being investigated in clinical trials. Recently, commercially available intravenous immunoglobulins (IVIG) have been used in small pilot trials for the treatment of patients with AD, based on the hypothesis that IVIG contains naturally occurring autoantibodies (nAbs-Abeta) that specifically recognize and block the toxic effects of Abeta. Furthermore, these nAbs-Abeta are reduced in AD patients compared with healthy controls, supporting the notion of replacement with IVIG. Beyond the occurrence of nAbs-Abeta, evidence for several other mechanisms associated with IVIG in AD has been reported in preclinical experiments and clinical studies. In 2009, a phase III clinical trial involving more than 360 AD patients was initiated and may provide conclusive evidence for the effect of IVIG as a treatment option for AD in 2011. In this article, we review the current knowledge and scientific rationale for using IVIG in patients with AD and other neurodegenerative disorders.
PMID: 20329802 [PubMed - indexed for MEDLINE]
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34.
Biochem Biophys Res Commun. 2010 Apr 2;394(2):393-7. Epub 2010 Mar 7.

Design and development of non-fibrillar amyloid beta as a potential Alzheimer vaccine.

Department of Neurochemistry, National Institute of Mental Health & Neurosciences, Bangalore 560029, India. sarada@nimhans.kar.nic.in

Abstract

Alzheimer's disease (AD) is the most common cause of dementia affecting the elderly. Treatment for effective cure of this complex neurodegenerative disease does not yet exist. In AD, otherwise soluble, monomeric form of amyloid beta (Abeta) peptide converts into toxic, fibrillar form rich in beta-sheet content. Several immunological approaches that prevent this conversion of Abeta into pathological form or that accelerate its clearance are being actively pursued worldwide. As part of these attempts, we report here, the design and characterization of a non-amyloidogenic homologue of Abeta (Abeta-KEK). We demonstrate that this peptide is helical in nature and retains the immunoneutralizing epitopes of native Abeta. More importantly, Fab fragments of the polyclonal anti-Abeta-KEK antibodies interfere with formation of Abeta fibrils as well as dissociate the preformed Abeta aggregates in vitro. These results suggest that non-amyloidogenic Abeta-KEK may serve as a safer alternative vaccine for Alzheimer's disease.
2010 Elsevier Inc. All rights reserved.
PMID: 20214884 [PubMed - indexed for MEDLINE]
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35.
CNS Neurol Disord Drug Targets. 2010 Apr;9(2):149-55.

Impact of the CD40-CD40L dyad in Alzheimer's disease.

Department of Psychiatry & Behavioral Medicine, Institute for Research in Psychiatry Neuroimmunology Laboratory, University of South Florida College of Medicine, Tampa, FL 33613, USA. bgiunta@health.usf.edu

Abstract

As the number of elderly individuals rises, Alzheimer's disease (AD), marked by amyloid-beta deposition, neurofibrillary tangle formation, and low-level neuroinflammation, is expected to lead to an ever-worsening socioeconomic burden. AD pathoetiologic mechanisms are believed to involve chronic microglial activation. This phenomenon is associated with increased expression of membrane-bound CD40 with its cognate ligand, CD40 ligand (CD40L), as well as increased circulating levels of soluble forms of CD40 (sCD40) and CD40L (sCD40L). Here, we review the role of this inflammatory dyad in the pathogenesis of AD. In addition, we examine potential therapeutic strategies such as statins, flavonoids, and human umbilical cord blood transplantation, all of which have been shown to modulate CD40-CD40L interaction in mouse models of AD. Importantly, therapeutic approaches focusing on CD40-CD40L dyad regulation, either alone or in combination with amyloid-beta immunotherapy, may provide for a safe and effective AD prophylaxis or treatment in the near future.
PMID: 20205645 [PubMed - indexed for MEDLINE]PMCID: PMC2892111Free PMC Article
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36.
CNS Neurol Disord Drug Targets. 2010 Apr;9(2):192-6.

Re-balancing of inflammation and abeta immunity as a therapeutic for Alzheimer's disease-view from the bedside.

Department of Medicine, UCLA School of Medicine, Los Angeles, CA, USA. fiala@mednet.ucla.edu

Abstract

Morbidities of aging and Alzheimer's disease (AD) have been related to defective functions of both T cells and macrophages leading to brain amyloidosis and inflammation. In AD patients, "inflammaging" may be associated with an increase of incompetent memory T cells and inflammatory cytokines produced by macrophages, whereas defective clearance of amyloid-beta 1-42 (Abeta) may be related to defective transcription of immune genes necessary for Abeta phagocytosis, beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase and Toll-like receptors. However, AD shows considerable heterogeneity of disease manifestations and mechanisms. The approaches to re-balancing Abeta immunity and inflammation are being pursued in transgenic animal models and peripheral blood mononuclear cells of patients. The regulatory signaling pathways of microglial phagocytosis and inflammation involving co-receptors and transforming growth factor-beta have been considerably clarified in animal studies. Natural immunostimulating therapies using vitamin D3 and curcuminoids have been developed in macrophages of AD patients. AD patients possess two types of macrophages: a majority has "Type I", which are improved by curcuminoids and vitamin D3; whereas a minority has "Type II" responding positively to vitamin D3 but not to curcuminoids. Other nutritional substances, such as plant polyphenols and omega-3 fatty acids, may inhibit inflammation and stimulate immunity. More invasive immune approaches involve Abeta vaccine and cytokine antagonists. Increased inflammation may represent the "first hit", and defective transcription of immune genes the "second hit" in the pathogenesis of AD.
PMID: 20205641 [PubMed - indexed for MEDLINE]
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37.
CNS Neurol Disord Drug Targets. 2010 Apr;9(2):197-206.

Amyloid-beta immunotherapy for Alzheimer's disease.

Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.

Abstract

Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. As the population grows and lifespan is extended, the number of AD patients will continue to rise. Current clinical therapies for AD provide partial symptomatic benefits for some patients; however, none of them modify disease progression. Amyloid-beta (Abeta) peptide, the major component of senile plaques in AD patients, is considered to play a crucial role in the pathogenesis of AD thereby leading to Abeta as a target for treatment. Abeta immunotherapy has been shown to induce a marked reduction in amyloid burden and an improvement in cognitive function in animal models. Although preclinical studies were successful, the initial human clinical trial of an active Abeta vaccine was halted due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Some encouraging outcomes, including signs of cognitive stabilization and apparent plaque clearance, were obtained in subset of patients who generated antibody titers. These promising preliminary data support further efforts to refine Abeta immunotherapy to produce highly effective and safer active and passive vaccines for AD. Furthermore, some new human clinical trials for both active and passive Abeta immunotherapy are underway. In this review, we will provide an update of Abeta immunotherapy in animal models and in human beings, as well as discuss the possible mechanisms underlying Abeta immunotherapy for AD.
PMID: 20205640 [PubMed - indexed for MEDLINE]PMCID: PMC2895488 [Available on 2011/4/1]
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38.
CNS Neurol Disord Drug Targets. 2010 Apr;9(2):207-16.

Abeta DNA vaccination for Alzheimer's disease: focus on disease prevention.

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, 92697-4540, USA. cribbs@uci.edu

Abstract

Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-Abeta antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which may increase the incidence of adverse events in the elderly population targeted to receive immunotherapy. The first active immunization clinical trial with AN1792 in AD patients was halted when a subset of patients developed meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Abeta, also encountered some dose dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers. The proposed remedy is to treat future patients with lower doses, particularly in the ApoE4 carriers. Currently there are at least five ongoing anti-Abeta immunotherapy clinical trials. Three of the clinical trials use humanized monoclonal antibodies, which are expensive and require repeated dosing to maintain therapeutic levels of the antibodies in the patient. However in the event of an adverse response to the passive therapy antibody delivery can simply be halted, which may provide a resolution to the problem. Because at this point we cannot readily identify individuals in the preclinical or prodromal stages of AD pathogenesis, passive immunotherapy is reserved for those that already have clinical symptoms. Unfortunately those individuals have by that point accumulated substantial neuropathology in affected regions of the brain. Moreover, if Abeta pathology drives tau pathology as reported in several transgenic animal models, and once established if tau pathology can become self propagating, then early intervention with anti-Abeta immunotherapy may be critical for favorable clinical outcomes. On the other hand, active immunization has several significant advantages, including lower cost and the typical immunization protocol should be much less intrusive to the patient relative to passive therapy, in the advent of Abeta-antibody immune complex-induced adverse events the patients will have to receive immuno-supperssive therapy for an extended period until the anti Abeta antibody levels drop naturally as the effects of the vaccine decays over time. Obviously, improvements in vaccine design are needed to improve both the safety, as well as the efficacy of anti-Abeta immunotherapy. The focus of this review is on the advantages of DNA vaccination for anti-Abeta immunotherapy, and the major hurdles, such as immunosenescence, selection of appropriate molecular adjuvants, universal T cell epitopes, and possibly a polyepitope design based on utilizing existing memory T cells in the general population that were generated in response to childhood or seasonal vaccines, as well as various infections. Ultimately, we believe that the further refinement of our AD DNA epitope vaccines, possibly combined with a prime boost regime will facilitate translation to human clinical trials in either very early AD, or preferably in preclinical stage individuals identified by validated AD biomarkers.
PMID: 20205639 [PubMed - indexed for MEDLINE]
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39.
IDrugs. 2010 Mar;13(3):162-5.

BioPartnering North America--Programs from Pharma in Europe and the Middle East.

Freelance Scientific Consultant, Vancouver, BC, Canada. leoniecroydon@gmail.com

Abstract

The BioPartnering North America conference, held in Vancouver, included presentations covering drug pipeline developments from both large and small pharmaceutical companies. This conference report highlights selected presentations from drug developers from Europe and the Middle East, specifically France, Spain, Denmark, Ireland, Sweden, Switzerland, Germany and Israel. Investigational drugs discussed include naproxcinod and NCX-116 (both NicOx SA), beta-amyloid (Abeta)40- and Abeta42-targeting vaccines (Araclon Biotech SI), ROSE-010 (Rose Pharma A/S), ADC-1004 (Alligator Bioscience AB), and VPM-4-001 (Vakzine Projekt Management GmbH).
PMID: 20191431 [PubMed - indexed for MEDLINE]
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40.
Nat Rev Neurol. 2010 Feb;6(2):108-19.

Can Alzheimer disease be prevented by amyloid-beta immunotherapy?

Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, New Research Building 636F, Boston, MA 02115, USA. clemere@rics.bwh.harvard.edu
Erratum in:
  • Nat Rev Neurol. 2010 Apr;6(4):183.
  • Nat Rev Neurol. 2010 Jun;6(6):296.

Abstract

Alzheimer disease (AD) is the most common form of dementia. The amyloid-beta (Abeta) peptide has become a major therapeutic target in AD on the basis of pathological, biochemical and genetic evidence that supports a role for this molecule in the disease process. Active and passive Abeta immunotherapies have been shown to lower cerebral Abeta levels and improve cognition in animal models of AD. In humans, dosing in the phase II clinical trial of the AN1792 Abeta vaccine was stopped when approximately 6% of the immunized patients developed meningoencephalitis. However, some plaque clearance and modest clinical improvements were observed in patients following immunization. As a result of this study, at least seven passive Abeta immunotherapies are now in clinical trials in patients with mild to moderate AD. Several second-generation active Abeta vaccines are also in early clinical trials. On the basis of preclinical studies and the limited data from clinical trials, Abeta immunotherapy might be most effective in preventing or slowing the progression of AD when patients are immunized before or in the very earliest stages of disease onset. Biomarkers for AD and imaging technology have improved greatly over the past 10 years and, in the future, might be used to identify presymptomatic, at-risk individuals who might benefit from Abeta immunization.
PMID: 20140000 [PubMed - indexed for MEDLINE]PMCID: PMC2864089Free PMC Article
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41.
Tohoku J Exp Med. 2010;220(2):95-106.

Immunization therapy for Alzheimer disease: a comprehensive review of active immunization strategies.

Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Juntendo University, Tokyo, Japan. spfe6he9@mild.ocn.ne.jp

Abstract

Based on the amyloid cascade hypothesis, various strategies targeting amyloid beta protein (Abeta) have been invented for prevention and treatment of Alzheimer disease (AD). Active and passive immunizations with Abeta and Abeta antibodies successfully reduced AD pathology and improved cognitive functions in an AD mouse model. However, active immunization with AN-1792, a mixture of Abeta1-42 peptide and adjuvant QS21 induced autoimmune encephalitis in humans. Surprisingly, although AN-1792 cleared senile plaque amyloid, it showed no benefit in humans. It is speculated that AN-1792 failed in deleting more toxic forms of Abeta such as oligomers and intracellular Abeta, suggesting that newly developing vaccines should delete these toxic molecules. Since T cell epitopes exist mainly in the C-terminal portion of Abeta, vaccines using shorter N-terminal peptides are under development. In addition, since T helper 1 (Th1) immune responses activate encephalitogenic T cells and induce continuous inflammation in the central nervous system, vaccines inducing Th2 immune responses seem to be more promising. These are N-terminal short Abeta peptides with Th2 adjuvant or Th2-stimulating molecules, DNA vaccines, recombinant viral vector vaccines, recombinant vegetables and others. Improvement of vaccines will be also achieved by the administration method, because Th2 immune responses are mainly induced by mucosal or trans-cutaneous immunizations. Here I review recent progress in active immunization strategies for AD.
PMID: 20139660 [PubMed - indexed for MEDLINE]Free Article
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42.
Biophys J. 2010 Jan 6;98(1):27-36.

Atomic-scale simulations confirm that soluble beta-sheet-rich peptide self-assemblies provide amyloid mimics presenting similar conformational properties.

Department of Chemical and Biomolecular Engineering, University of Akron, Akron, Ohio, USA.

Abstract

The peptide self-assembly mimic (PSAM) from the outer surface protein A (OspA) can form highly stable but soluble beta-rich self-assembly-like structures similar to those formed by native amyloid-forming peptides. However, unlike amyloids that predominantly form insoluble aggregates, PSAMs are highly water-soluble. Here, we characterize the conformations of these soluble beta-sheet-rich assemblies. We simulate PSAMs with different-sized beta-sheets in the presence and absence of end-capping proteins using all-atom explicit-solvent molecular dynamics, comparing the structural stability, conformational dynamics, and association force. Structural and free-energy comparisons among beta-sheets with different numbers of layers and sequences indicate that in similarity to amyloids, the intersheet side chain-side chain interactions and hydrogen bonds combined with intrasheet salt bridges are the major driving forces in stabilizing the overall structural organization. A detailed structural analysis shows that in similarity to amyloid fibrils, all wild-type and mutated PSAM structures display twisted and bent beta-sheets to some extent, implying that a twisted and bent beta-sheet is a general motif of beta-rich assemblies. Thus, our studies indicate that soluble beta-sheet-rich peptide self-assemblies can provide good amyloid mimics, and as such confirm on the atomic scale that they are excellent systems for amyloid studies. These results provide further insight into the usefulness of such mimics for nanostructure design.
Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.
PMID: 20085717 [PubMed - indexed for MEDLINE]PMCID: PMC2800962Free PMC Article
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43.
J Neuroimmune Pharmacol. 2010 Mar;5(1):133-42.

Virus-like peptide vaccines against Abeta N-terminal or C-terminal domains reduce amyloid deposition in APP transgenic mice without addition of adjuvant.

Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA.

Abstract

Immunotherapy against the Abeta peptide is increasingly viewed as an effective means of preventing and even decreasing Abeta deposition in transgenic mouse models and human cases of Alzheimer's disease. A prior active immunization trial was halted due to adverse events which occurred subsequent to a change in the adjuvant used in the vaccine preparation. Although widely used in experimental studies, adjuvants available for use in vaccines intended for humans are limited. We compared two vaccine preparations in which an immunogenic bacteriophage was conjugated with either an N-terminal (Abeta1-9) or C-terminal (Abeta28-40) peptide sequence from the Abeta molecule. We found that both produced significant antibody titers without use of additional adjuvants. Surprisingly, the response to the N terminal sequence was comprised largely of a stable IgM response, while the C-terminal vaccine produced an IgG response with minimal IgM reactivity. Both of these immunogens reduced Abeta levels when tissues were examined 8 months after the first inoculation. These data demonstrate that (a) C-terminal specific vaccines can effectively lower Abeta and (b) IgM antibodies against Abeta may be capable of lowering Abeta, possibly through action in the brain rather than the periphery.
PMID: 20066498 [PubMed - indexed for MEDLINE]
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44.
MAbs. 2009 Mar-Apr;1(2):112-4. Epub 2009 Mar 11.

Immunotherapy for Alzheimer disease.

Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA. gkgouras@med.cornell.edu

Abstract

Immunotherapy approaches for Alzheimer disease currently are among the leading therapeutic directions for the disease. Active and passive immunotherapy against the beta-amyloid peptides that aggregate and accumulate in the brain of those afflicted by the disease have been shown by numerous groups to reduce plaque pathology and improve behavior in transgenic mouse models of the disease. Several ongoing immunotherapy clinical trials for Alzheimer disease are in progress. The background and ongoing challenges for these immunological approaches for the treatment of Alzheimer disease are discussed.
PMID: 20061820 [PubMed - indexed for MEDLINE]PMCID: PMC2725424Free PMC Article
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45.
Rinsho Shinkeigaku. 2009 Nov;49(11):848-50.

[Vaccination therapy for Alzheimer's disease].

[Article in Japanese]
Department of Diagnosis, Prevention and Treatment of Dementia, Graduate School of Juntendo University.

Abstract

Since AN-1792 vaccine induced autoimmune encephalitis, several pharmaceutical companies are now concentrated in developing antibody therapy in Alzheimer's disease (AD). Each antibody has own characteristics. Thus, it is unpredictable at present which antibody is the most beneficial until we see the result of clinical trials. If disease modifying antibodies were found, they will be widely used for treatment of AD in near future. As a candidate of such antibodies, we have developed TAPIR-like antibody with much higher affinity to Abeta42 than Abeta40, and it effectively deleted senile plaque amyloid and Abeta oligomers without increasing microhemorrhages. Although passive immunization can avoid autoimmune encephalitis, it is expensive and it is not suitable for prevention. Thus, safe vaccines by active immunization would be better. Vaccines that induce Th2 type immune responses such as oral vaccine or per-nasal vaccine would be promising.
PMID: 20030228 [PubMed - indexed for MEDLINE]
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46.
Brain Struct Funct. 2010 Mar;214(2-3):201-18. Epub 2009 Dec 10.

Immunotherapeutic approaches for Alzheimer's disease in transgenic mouse models.

Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA. thomas.wisniewski@nyumc.org

Abstract

Alzheimer's disease (AD) is a member of a category of neurodegenerative diseases characterized by the conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it resistant to degradation and neurotoxic. In the case of AD the normal soluble amyloid beta (sAbeta) peptide is converted into oligomeric/fibrillar Abeta. The oligomeric forms of Abeta are thought to be the most toxic, while fibrillar Abeta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is an essential part of the pathology. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror different aspects of AD pathology. Perhaps the most exciting of these approaches is immunomodulation. Vaccination is currently being tried for a range of age associated CNS disorders with great success being reported in many transgenic mouse models. However, there is a discrepancy between these results and current human clinical trials which highlights the limitations of current models and also uncertainties in our understanding of the underlying pathogenesis of AD. No current AD Tg mouse model exactly reflects all aspects of the human disease. Since the underlying etiology of sporadic AD is unknown, the process of creating better Tg models is in constant evolution. This is an essential goal since it will be necessary to develop therapeutic approaches which will be highly effective in humans.
PMID: 20012091 [PubMed - indexed for MEDLINE]
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47.
J Neuroimmunol. 2010 Feb 26;219(1-2):8-16. Epub 2009 Dec 3.

Tetravalent Abeta1-15 vaccine reduces TCR-positive cell infiltration and up-regulates p75 in Tg2576 brains compared to Abeta42 vaccine.

Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou Guangdong Province 510080, PR China. vip.lihui@gzhtcm.edu.cn

Abstract

In order to investigate the effect of Abeta vaccines on T cell infiltration into the brain, we immunized Tg2576 mice with two adenovirus vaccines containing tetravalent Abeta1-15 (4xAbeta15) or Abeta42. TCR-positive cells were found in the ventricle, parenchyma, and surrounding the vasculature, especially concentrating in the periventricular parenchyma, the reticular part of the substantia nigra and the corpus striatum. Compared to the Abeta42 group, TCR-positive cells in the tetravalent (4x) Abeta15 group were significantly decreased. Both vaccines down-regulated neurotrophic and inflammatory factors, but the 4xAbeta15 vaccine up-regulated TrkA and p75 compared with the Abeta42 vaccine. The results suggest that the 4xAbeta15 vaccine might be safer and more beneficial than the Abeta42 vaccine.
Copyright 2009. Published by Elsevier B.V.
PMID: 19962199 [PubMed - indexed for MEDLINE]
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48.
Gene Ther. 2010 Feb;17(2):261-71. Epub 2009 Oct 29.

DNA prime-protein boost increased the titer, avidity and persistence of anti-Abeta antibodies in wild-type mice.

Department of Molecular Immunology, The Institute for Molecular Medicine, Huntington Beach, CA 92647-3652, USA.

Abstract

Recently, we reported that a DNA vaccine, composed of three copies of a self B cell epitope of amyloid-beta (Abeta(42)) and the foreign T-cell epitope, Pan DR epitope (PADRE), generated strong anti-Abeta immune responses in wild-type and amyloid precursor protein transgenic animals. Although DNA vaccines have several advantages over peptide-protein vaccines, they induce lower immune responses in large animals and humans compared with those in mice. The focus of this study was to further enhance anti-Abeta(11) immune responses by developing an improved DNA vaccination protocol of the prime-boost regimen, in which the priming step would use DNA and the boosting step would use recombinant protein. Accordingly, we generated DNA and recombinant protein-based epitope vaccines and showed that priming with DNA followed by boosting with a homologous recombinant protein vaccine significantly increases the anti-Abeta antibody responses and do not change the immunoglobulin G1 (IgG1) profile of humoral immune responses. Furthermore, the antibodies generated by this prime-boost regimen were long-lasting and possessed a higher avidity for binding with an Abeta(42) peptide. Thus, we showed that a heterologous prime-boost regimen could be an effective protocol for developing a potent Alzheimer's disease (AD) vaccine.
PMID: 19865176 [PubMed - indexed for MEDLINE]PMCID: PMC2820600Free PMC Article
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49.
JAMA. 2009 Oct 28;302(16):1796-802.

DNA beta-amyloid(1-42) trimer immunization for Alzheimer disease in a wild-type mouse model.

Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9108, USA.

Abstract

CONTEXT: DNA beta-amyloid(1-42) (Abeta42) trimer immunization was developed to produce specific T helper 2 cell (T(H)2)-type antibodies to provide an effective and safe therapy for Alzheimer disease (AD) by reducing elevated levels of Abeta42 peptide that occur in the brain of patients with AD.
OBJECTIVE: To compare the immune response in wild-type mice after immunization with DNA Abeta42 trimer and Abeta42 peptide.
DESIGN AND INTERVENTION: Wild-type mice received either 4 microg of DNA Abeta42 trimer immunization administered with gene gun (n = 8) or intraperitoneal injection of 100 microg of human Abeta42 peptide with the adjuvant Quil A (n = 8). Titers, epitope mapping, and isotypes of the Abeta42-specific antibodies were analyzed.
MAIN OUTCOME MEASURES: Antibody titers, mapping of binding sites (epitopes), isotype profiles of the Abeta42-specific antibodies, and T-cell activation.
RESULTS: DNA Abeta42 trimer immunization resulted in antibody titers with a mean of 15 microg per milliliter of plasma. The isotype profile of the antibodies differed markedly. A predominant IgG1 antibody response was found in the DNA-immunized mice, indicating a T(H)2 type of immune response (IgG1/IgG2a ratio of 10). The peptide-immunized mice showed a mixed T(H)1/T(H)2 immune response (IgG1/IgG2a ratio of 1) (P < .001). No increased T-cell proliferation was observed in the DNA-immunized mice (P = .03).
CONCLUSION: In this preliminary study in a wild-type mouse model, DNA Abeta42 trimer immunization protocol produced a T(H)2 immune response and appeared to have low potential to cause an inflammatory T-cell response.
PMID: 19861672 [PubMed - indexed for MEDLINE]PMCID: PMC2896011Free PMC Article
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50.
J Alzheimers Dis. 2009;18(4):961-72.

Diminished amyloid-beta burden in Tg2576 mice following a prophylactic oral immunization with a salmonella-based amyloid-beta derivative vaccine.

Department of Physiology and Neuroscience, New York University School of Medicine, New York, NY 10016, USA.

Abstract

Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. Prior to the side effects in the first Elan/Wyeth AD vaccine trial, we proposed using amyloid-beta (Abeta) derivatives as a safer approach. The route of administration may also affect vaccine safety. To assess the feasibility of oral immunization that promotes mucosal immunity, Tg2576 AD model mice were treated prophylactically three times over 6 weeks starting at 3-5 months of age with a Salmonella vaccine expressing K6Abeta(1-30). At 22-24 months of age, cortical Abeta plaque burden and total Abeta(40/42) levels were reduced by 48-75% in the immunized mice compared to controls, which received unmodified Salmonella. Plaque clearance was not associated with increased microglial activation, which may be explained by the long treatment period. Furthermore, cerebral microhemorrhages were not increased in the treated mice in contrast to several passive Abeta antibody studies. These results further support our findings with this immunogen delivered subcutaneously and demonstrate its efficacy when given orally, which may provide added benefits for human use.
PMID: 19749432 [PubMed - indexed for MEDLINE]PMCID: PMC2842483Free PMC Article
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51.
Neuropsychopharmacol Hung. 2009 Mar;11(1):27-33.

[Therapy of Alzheimer disease].

[Article in Hungarian]
Semmelweis Egyetem AOK, Neuroló giai Klinika, Budapest. tibor@neur.sote.hu

Abstract

Dementia is one of the most important health problems in the aging populations. The most frequent cause of it is Alzheimer's disease (AD) which is characterized by intracellular neuro-fibrillary tangles (NFT) and the extracellular senile plaques. The NFTs are mainly formed by the hyperphosphorylated microtubule-binding protein, the tau, while the senile plaques are composed of beta-amyloid protein cleaved from the amyloid precursor protein (APP) by the beta- and gamma-secretases. The pharmacotherapy of AD consists of symptomatic and disease-modifying therapies. The most frequently used therapeutic agents are the nootropic drugs supported by personal rather evidence based experiences. The leading-edge therapy of AD at present is the inhibition of the acetylcholine-esterase enzyme (AChEI) with mainly cognitive symptomatic and weak disease-modifying effects; they are licensed in the mild and middle stages of AD (MMSE 26-10), but their effect is proved in the severe stage of the disease and they are effective in the management of the neuropsychiatric symptoms too. Memantine (which is an inhibitor of the N-metil-D-aspartate receptor) is used in the middle and severe stages of AD and it can be effectively combined with AChEIs. The future therapy of AD will possibly be a "causative" therapy. The most frequent directions are therapies aiming to decrease the production or the deposition of beta-amyloid peptide. The active vaccination study of AN-1792 was terminated because of immunological side-effects, but several active and passive immunisation therapies are in development nowadays. It is also possible to inhibit the aggregation of the beta-amyloid peptide with peptide fragments or with Cu2+ and Zn2+ ion chelators. A promising direction is the inhibition of the enzymes responsible for the production of the beta-amyloid peptide: beta-secretase inhibitors with low molecular weight and penetrability through the blood-brain barrier are developed while the inhibitors of the gamma-secretase (some of them are the derivatives of the non-steroid anti-inflammatory drug ibuprofen) are tested in phase III trials. The inhibition of NFT formation might be promising too and inhibitors of the enzymes responsible for the hyperphosphorylation of the tau (like the glycogen synthase kinase-3) are in develo ment. Several other therapeutic methods are studied. NSAIDs and statins are useful in the prevention of the disease but they are failed in symptomatic treatment. There are promising studies in few patients using nerve growth factor therapy and some studies proved that peroxisome proliferator activated receptor (PPAR) agonist rosiglitazone (which is used to the treat diabetes mellitus) is effective in AD. The presently modest therapeutic interventions of AD will explode in the near future and together with the improved diagnostics of the disease they will cause further specialization with increased treatment and caring costs amplified by the ever growing number of the patients. This means that AD is and will be one of the most important diseases for the health care systems.
PMID: 19731816 [PubMed - indexed for MEDLINE]
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53.
Prog Brain Res. 2009;175:83-93.

Developing novel immunogens for a safe and effective Alzheimer's disease vaccine.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. clemere@rics.bwh.harvard.edu

Abstract

Alzheimer's disease (AD) is the most prevalent form of neurodegeneration; however, therapies to prevent or treat AD are inadequate. Amyloid-beta (Abeta) protein accrues in cortical senile plaques, one of the key neuropathological hallmarks of AD, and is elevated in brains of early onset AD patients in a small number of families that bear certain genetic mutations, further implicating its role in this devastating neurological disease. In addition, soluble Abeta oligomers have been shown to be detrimental to neuronal function. Therapeutic strategies aimed at lowering cerebral Abeta levels are currently under development. One strategy is to immunize AD patients with Abeta peptides so that they will generate antibodies that bind to Abeta protein and enhance its clearance. As of 1999, Abeta immunotherapy, either through active immunization with Abeta peptides or through passive transfer of Abeta-specific antibodies, has been shown to reduce cerebral Abeta levels and improve cognitive deficits in AD mouse models and lower plaque load in nonhuman primates. However, a Phase II clinical trial of active immunization using full-length human Abeta1-42 peptide and a strong Th1-biased adjuvant, QS-21, ended prematurely in 2002 because of the onset of meningoencephalitis in approximately 6% of the AD patients enrolled in the study. It is possible that T cell recognition of the human full-length Abeta peptide as a self-protein may have induced an adverse autoimmune response in these patients. Although only approximately 20% of immunized patients generated anti-Abeta titers, responders showed some general slowing of cognitive decline. Focal cortical regions devoid of Abeta plaques were observed in brain tissues of several immunized patients who have since come to autopsy. In order to avoid a deleterious immune response, passive Abeta immunotherapy is under investigation by administering monthly intravenous injections of humanized Abeta monoclonal antibodies to AD patients. However, a safe and effective active Abeta vaccine would be more cost-effective and more readily available to a larger AD population. We have developed several novel short Abeta immunogens that target the Abeta N-terminus containing a strong B cell epitope while avoiding the Abeta mid-region and C-terminus containing T cell epitopes. These immunogens include dendrimeric Abeta1-15 (16 copies of Abeta1-15 on a lysine antigen tree), 2xAbeta1-15 (a tandem repeat of two lysine-linked Abeta1-15 peptides), and 2xAbeta1-15 with the addition of a three amino acid RGD motif (R-2xAbeta1-15). Intranasal immunization with our short Abeta fragment immunogens and a mucosal adjuvant, mutant Escherichia coli heat-labile enterotoxin LT(R192G), resulted in reduced cerebral Abeta levels, plaque deposition, and gliosis, as well as increased plasma Abeta levels and improved cognition in a transgenic mouse model of AD. Preclinical trials in nonhuman primates, and human clinical trials using similar Abeta immunogens, are now underway. Abeta immunotherapy looks promising but must be made safer and more effective at generating antibody titers in the elderly. It is hoped that these novel immunogens will enhance Abeta antibody generation across a broad population and avoid the adverse events seen in the earlier clinical trial.
PMID: 19660650 [PubMed - indexed for MEDLINE]PMCID: PMC2814339Free PMC Article
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54.
AAPS PharmSciTech. 2009;10(3):900-5. Epub 2009 Jul 16.

Amyloid-beta associated with chitosan nano-carrier has favorable immunogenicity and permeates the BBB.

Department of Physiology, Xiangya Medical College, Central South University, Changsha 410078, China.

Abstract

Subfragments of amyloid-beta (Abeta) appear to protect neurons from Alzheimer's disease (AD). The permeability of the blood-brain barrier (BBB) has limited in vivo research. The aim of this study is to explore permeation of the BBB by chitosan nanoparticles loaded with Abeta and to evaluate immunogenicity of these particles. Chitosan microspheres were prepared by mechanical stirring emulsification methods combined with chemical crosslinking. Morphological characteristics of the nanoparticles were examined using high-resolution transmission electron microscopy. The peptide association efficiency was determined by high-performance liquid chromatography. Fluorescently labeled chitosan nanoparticle-intramembranous fragments of Abeta (NP-IF-A) were administered systemically to mice in order to evaluate brain translocation by fluorescence microscopy. The immunogenicity of the nano-vaccine was determined by enzyme-linked immunosorbent assay (ELISA). All nanoparticles analyzed were well-separated, roughly spherical structures with uniform particle size distribution in the range of 15.23 +/- 10.97 nm. The peptide association efficiency was 78.4%. The brain uptake efficiency of nano-antigen was 80.6%; uptake efficiency of antigen alone was only 20.6%. ELISA showed that the nano-vaccine had favorable immunogenicity. A chitosan nano-carrier for Abeta allowed permeation of the BBB and was non-immunogenic. These findings indicate that this novel targeted nano-vaccine delivery system can be used as a carrier for Abeta. This system will further research of peptide vaccines for AD.
PMID: 19609682 [PubMed - indexed for MEDLINE]PMCID: PMC2802149Free PMC Article
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56.
J Neurosci. 2009 Jun 24;29(25):7957-65.

Amyloid reduction by amyloid-beta vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease.

Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. donna.wilcock@duke.edu
Erratum in:
  • J Neurosci. 2010 Jan 20;30(3):1197-8.

Abstract

Shown to lower amyloid deposits and improve cognition in APP transgenic mouse models, immunotherapy appears to be a promising approach for the treatment of Alzheimer's disease (AD). Due to limitations in available animal models, however, it has been unclear whether targeting amyloid is sufficient to reduce the other pathological hallmarks of AD-namely, accumulation of pathological, nonmutated tau and neuronal loss. We have now developed two transgenic mouse models (APPSw/NOS2(-/-) and APPSwDI/NOS2(-/-)) that more closely model AD. These mice show amyloid pathology, hyperphosphorylated and aggregated normal mouse tau, significant neuron loss, and cognitive deficits. A beta(1-42) or KLH vaccinations were started in these animals at 12 months, when disease progression and cognitive decline are well underway, and continued for 4 months. Vaccinated APPSwDI/NOS2(-/-) mice, which have predominantly vascular amyloid pathology, showed a 30% decrease in brain A beta and a 35-45% reduction in hyperphosphorylated tau. Neuron loss and cognitive deficits were partially reduced. In APPSw/NOS2(-/-) vaccinated mice, brain A beta was reduced by 65-85% and hyperphosphorylated tau by 50-60%. Furthermore, neurons were completely protected, and memory deficits were fully reversed. Microhemorrhage was observed in all vaccinated APPSw/NOS2(-/-) mice and remains a significant adverse event associated with immunotherapy. Nevertheless, by providing evidence that reducing amyloid pathology also reduces nonmutant tau pathology and blocks neuron loss, these data support the development of amyloid-lowering therapies for disease-modifying treatment of AD.
PMID: 19553436 [PubMed - indexed for MEDLINE]PMCID: PMC2871319Free PMC Article
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57.
J Neuroimmunol. 2009 Aug 18;213(1-2):39-46. Epub 2009 Jul 9.

Immunodominant epitope and properties of pyroglutamate-modified Abeta-specific antibodies produced in rabbits.

Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), AP 70228, Cuidad Universitaria, México DF, 04510, Mexico.

Abstract

N-truncated and N-modified forms of amyloid beta (Abeta) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as well as transgenic mouse models of AD. Although the pathological significance of these shortened forms Abeta is not completely understood, previous studies have demonstrated that these peptides are significantly more resistant to degradation, aggregate more rapidly in vitro and exhibit similar or, in some cases, increased toxicity in hippocampal neuronal cultures compared to the full length peptides. In the present study we further investigated the mechanisms of toxicity of one of the most abundant N-truncated/modified Abeta peptide bearing amino-terminal pyroglutamate at position 3 (AbetaN3(pE)). We demonstrated that AbetaN3(pE) oligomers induce phosphatidyl serine externalization and membrane damage in SH-SY5Y cells. Also, we produced AbetaN3(pE)-specific polyclonal antibodies in rabbit and identified an immunodominant epitope recognized by anti-AbetaN3(pE) antibodies. Our results are important for developing new immunotherapeutic compounds specifically targeting AbetaN3(pE) aggregates since the most commonly used immunogens in the majority of vaccines for AD have been shown to induce antibodies that recognize the N-terminal immunodominant epitope (EFRH) of the full length Abeta, which is absent in N-amino truncated peptides.
PMID: 19545911 [PubMed - indexed for MEDLINE]PMCID: PMC2725226Free PMC Article
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58.
Trends Immunol. 2009 Jul;30(7):344-50. Epub 2009 Jun 21.

Immune therapy for age-related diseases.

Department of Medicine, Weill-Cornell Medical College, NY 10065, USA. weksler@med.cornell.edu

Abstract

Human aging is reaching epidemic proportions as life expectancy increases and birth rate decreases. These demographic trends have led to a sharp increase in the diseases of aging, and an understanding of immune senescence promises to limit the development and progression of these diseases. In this review, we discuss three of the most important diseases of aging: shingles, Alzheimer's disease and atherosclerotic cardiovascular disease. All of these diseases have significant immunological components in either their etiology and/or progression, suggesting that appropriate immune intervention could be used in their prevention or treatment. Indeed, recent clinical studies have already demonstrated that vaccination can reduce the incidence of shingles and might prove effective in patients with Alzheimer's disease and artherosclerotic cardiovascular disease.
PMID: 19541533 [PubMed - indexed for MEDLINE]
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59.
Mol Immunol. 2009 Aug;46(13):2524-32. Epub 2009 Jun 16.

Immunogenic, antigenic, fibrillogenic and inflammatory properties of new simplified beta-amyloid peptides.

Tecnogen S.p.A., R&D, Caserta, Italy.

Abstract

The most promising approach in Alzheimer disease immunotherapy is represented by amyloid beta derivatives with low intrinsic neurotoxicity and minimal overall T cell responses. To avoid toxicity and autoimmune response, we have designed a new class of Abeta derivatives through segmentation of the original Abeta[1-42] peptide and application of the glycine substitution modification technology. Abeta[1-16], Abeta[13-28] and Abeta[25-42] fragments were selected in order to retain the major immunogenic sites of the Abeta[1-42] peptide. All peptides showed comparable immunogenicity, and raised antibodies were all able to cross-recognize both Abeta[1-42] and Abeta[1-40] synthetic amyloid forms. Polyclonal antibodies produced against the simplified variants were able to recognize the parent peptide, but not the opposite simplified forms, in strict agreement with the model of independent surfaces of recognition. All Abeta simplified derivatives showed reduced fibrillogenic properties, thus underlining that the introduction of glycine residues in alternating positions allows to obtain modified peptides maintaining the main immunogenic properties of the parent peptides, but with reduced ability to adopt a beta-sheet conformation and therefore a much lower risk of toxicity in humans. In addition, in vitro studies on peripheral blood mononuclear cells (PBMCs) from healthy donors showed that only the Abeta[13-28]+G peptide failed to induce IFN-gamma production, thus suggesting that this molecule could represent a good candidate for potentially safer vaccine therapy to reduce amyloid burden in Alzheimer's disease instead of using toxic Abeta[1-42].
PMID: 19535144 [PubMed - indexed for MEDLINE]
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60.
J Immunol. 2009 Jun 15;182(12):7613-24.

Vaccination with Abeta-displaying virus-like particles reduces soluble and insoluble cerebral Abeta and lowers plaque burden in APP transgenic mice.

Div of Immunology, Paul-Ehrlich-Institut, Langen, Germany.

Abstract

In transgenic animal models, humoral immunity directed against the beta-amyloid peptide (Abeta), which is deposited in the brains of AD patients, can reduce Abeta plaques and restore memory. However, initial clinical trials using active immunization with Abeta1-42 (plus adjuvant) had to be stopped as a subset of patients developed meningoencephalitis, likely due to cytotoxic T cell reactions against Abeta. Previously, we demonstrated that retrovirus-like particles displaying on their surface repetitive arrays of self and foreign Ags can serve as potent immunogens. In this study, we generated retrovirus-like particles that display the 15 N-terminal residues of human Abeta (lacking known T cell epitopes) fused to the transmembrane domain of platelet-derived growth factor receptor (Abeta retroparticles). Western blot analysis, ELISA, and immunogold electron microscopy revealed efficient incorporation of the fusion proteins into the particle membrane. Without the use of adjuvants, single immunization of WT mice with Abeta retroparticles evoked high and long-lived Abeta-specific IgG titers of noninflammatory Th2 isotypes (IgG1 and IgG2b) and led to restimulatable B cell memory. Likewise, immunization of transgenic APP23 model mice induced comparable Ab levels. The CNS of immunized wild-type mice revealed neither infiltrating lymphocytes nor activated microglia, and no peripheral autoreactive T cells were detectable. Importantly, vaccination not only reduced Abeta plaque load to approximately 60% of controls and lowered both insoluble Abeta40 as well as Abeta42 in APP23 brain, but also significantly reduced cerebral soluble Abeta species. In summary, Abeta retroparticle vaccination may thus hold promise as a novel efficient future candidate vaccine for active immunotherapy of Alzheimer's disease.
PMID: 19494285 [PubMed - indexed for MEDLINE]Free Article
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61.
J Neurochem. 2009 Aug;110(4):1129-34. Epub 2009 May 18.

The amyloid hypothesis for Alzheimer's disease: a critical reappraisal.

Reta Lilla Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK. j.hardy@ion.ucl.ac.uk

Abstract

The amyloid hypothesis has been the basis for most work on the pathogenesis of Alzheimer's disease. Recent clinical trials based on this hypothesis have been inconclusive. In this article I review the current status of the hypothesis and suggest that a major scientific need is to understand the normal function of amyloid-beta precursor protein (APP) and think how this may relate to the cell death in the disease process.
PMID: 19457065 [PubMed - indexed for MEDLINE]
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62.
Mol Biochem Parasitol. 2009 Aug;166(2):159-71. Epub 2009 Apr 9.

Plasmodium falciparum merozoite surface protein 2 is unstructured and forms amyloid-like fibrils.

Department of Biochemistry, La Trobe University, Victoria 3086, Australia.

Abstract

Several merozoite surface proteins are being assessed as potential components of a vaccine against Plasmodium falciparum, the cause of the most serious form of human malaria. One of these proteins, merozoite surface protein 2 (MSP2), is unusually hydrophilic and contains tandem sequence repeats, characteristics of intrinsically unstructured proteins. A range of physicochemical studies has confirmed that recombinant forms of MSP2 are largely unstructured. Both dimorphic types of MSP2 (3D7 and FC27) are equivalently extended in solution and form amyloid-like fibrils although with different kinetics and structural characteristics. These fibrils have a regular underlying beta-sheet structure and both fibril types stain with Congo Red, but only the FC27 fibrils stain with Thioflavin T. 3D7 MSP2 fibrils seeded the growth of fibrils from 3D7 or FC27 MSP2 monomer indicating the involvement of a conserved region of MSP2 in fibril formation. Consistent with this, digestion of fibrils with proteinase K generated resistant peptides, which included the N-terminal conserved region of MSP2. A monoclonal antibody that reacted preferentially with monomeric recombinant MSP2 did not react with the antigen in situ on the merozoite surface. Glutaraldehyde cross-linking of infected erythrocytes generated MSP2 oligomers similar to those formed by polymeric recombinant MSP2. We conclude that MSP2 oligomers containing intermolecular beta-strand interactions similar to those in amyloid fibrils may be a component of the fibrillar surface coat on P. falciparum merozoites.
PMID: 19450733 [PubMed - indexed for MEDLINE]PMCID: PMC2713819Free PMC Article
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64.
J Comp Neurol. 2009 Jul 1;515(1):4-14.

Development of vaccination approaches for the treatment of neurological diseases.

Department of Neurology, Georgetown University, Washington DC 20057, USA. hjf8@georgetown.edu

Abstract

Several progressive neurodegenerative diseases share a common pathology: the accumulation of misfolded proteins within cells or neuropil of the brain. Characteristically, these misfolded proteins form organized beta-sheet-containing assemblies that have optical and biochemical properties of amyloid. Thus, the brain amyloidoses, Alzheimer's disease (AD), Parkinson's disease, and the prionoses or transmissible spongioform encelphalopathies (TSEs) all manifest putatively pathogenic misfolded proteins, suggesting that these proteins or their precursors may be targets for therapeutics development efforts. Two different biological approaches, both predicated on vaccination, are discussed in this monograph as preclinical approaches for the treatment of AD and a TSE. Herein, I first describe an active vaccination approach that exploits immune shaping to engender a prophylactic T(H)2 response to Abeta in AD mouse models. Second, I describe a passive vaccination strategy whereby recombinant adeno-associated virus vectored delivery of anti-prion single-chain fragment variable antibodies attenuates disease progression and promotes life extension in a mouse TSE model.
Copyright 2009 Wiley-Liss, Inc.
PMID: 19399901 [PubMed - indexed for MEDLINE]
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66.
CNS Neurol Disord Drug Targets. 2009 Apr;8(2):128-43.

Rationale for peptide and DNA based epitope vaccines for Alzheimer's disease immunotherapy.

The Institute for Molecular Medicine, Department of Immunology, Huntington Beach, CA 92647, USA. aghochikyan@immed.org

Abstract

Amyloid-beta (Abeta) immunotherapy has received considerable attention as a promising approach for reducing the level of Abeta in the CNS of Alzheimer's disease patients. However, the first Phase II clinical trial, for the immune therapy AN1792, was halted when a subset of those immunized with Abeta(42) developed adverse events in the central nervous system. In addition, data from the trial indicated that there was a low percentage of responders and generally low to moderate titers in the patients that received the vaccine. Generated antibodies reduced beta-amyloid deposits in the parenchyma of patients' brains, but no reduction in soluble Abeta or significant improvements in cognitive function of patients were observed. These data and data from pre-clinical studies suggest that reduction in the most toxic oligomeric forms of Abeta is important for prevention or slowing down of the progression of cognitive decline, and that vaccination should be started prior to irreversible accumulation of the oligomeric Abeta, at the early stages of AD. Protective immunotherapy requires a development of safe and effective strategy for Abeta immunotherapy. In this review, the rationale for developing epitope vaccines for the treatment of AD will be discussed. We believe that an epitope vaccine will induce an adequate anti-Abeta antibody response in the absence of potentially adverse self T cell-mediated events, making it possible to start immunization at the early stages of AD.
PMID: 19355933 [PubMed - indexed for MEDLINE]PMCID: PMC2818979Free PMC Article
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67.
CNS Neurol Disord Drug Targets. 2009 Apr;8(2):114-27.

Alternative Abeta immunotherapy approaches for Alzheimer's disease.

Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. terrence.town@cshs.org

Abstract

In a seminal report in 1999, Schenk and colleagues demonstrated that vaccination of a mouse model of Alzheimer's disease (AD) with amyloid-beta(1-42) peptide (Abeta(1-42)) and adjuvant resulted in striking mitigation of AD-like pathology - giving rise to the field of AD immunotherapy. Later studies confirmed this result in other mouse models of AD and additionally showed cognitive improvement after Abeta vaccination. Based on these results, early developmental clinical trials ensued to immunize AD patients with Abeta(1-42) plus adjuvant (so-called "active" Abeta immunotherapy; trade name AN-1792; Elan Pharmaceuticals, Dublin, Ireland). However, the phase IIa trial was halted after 6 % of patients developed aseptic meningoencephalitis. Despite occurrence of this adverse event, many individuals demonstrated high serum antibody titres to Abeta and histological evidence of clearance of the hallmark AD pathology, beta-amyloid plaques. While raising justifiable safety concerns, these important results nonetheless demonstrated the feasibility of the active Abeta immunotherapy approach. This review focuses on alternative approaches to active Abeta vaccination that are currently in various stages of development - from pre-clinical studies in animal models to current clinical trials. Specifically, the focus is on those strategies that target inflammatory and immune aspects of AD, and can therefore be classified as immunotherapeutic in a broad sense.
PMID: 19355932 [PubMed - indexed for MEDLINE]PMCID: PMC2712251Free PMC Article
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68.
CNS Neurol Disord Drug Targets. 2009 Apr;8(2):98-113.

Immunotherapy in a natural model of Abeta pathogenesis: the aging beagle.

Institute for Brain Aging & Dementia, University of California, Irvine, CA 92697-4540, USA.

Abstract

Alzheimer disease (AD) is the most common form of dementia in the elderly and the number of individuals developing the disease is rapidly rising. Interventions focused on reducing beta-amyloid (Abeta), a component of senile plaques within the AD brain offer a promising approach to prevent or slow disease progression. In this review, we describe the immune system and cognitive and neurobiological features of a natural model of human brain aging, the beagle. The immune system of dogs shares many features of the human immune system, including developmental and aging characteristics. Further, dogs naturally accumulate human sequence Abeta as they age, which coincides with declines in learning and memory. A longitudinal study (approximately 2 years) of the response of aged beagles to vaccination with fibrillar Abeta1-42 indicated that despite significant clearance of Abeta, there were limited benefits in cognitive function. However, there was evidence for maintenance of executive function over time. These results are strikingly similar to reports of human clinical immunotherapy trials. We propose that the canine model complements existing animal models and will be helpful in developing new vaccine approaches to slowing or preventing Abeta pathology that can be translated to human clinical trials.
PMID: 19355931 [PubMed - indexed for MEDLINE]
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69.
Neurochem Res. 2009 Nov;34(11):1889-95. Epub 2009 Apr 4.

Intramembranous fragment of amyloid-beta: A potential immunogen for Alzheimer's disease immunotherapy.

Department of Physiology, Central South University, Changsha, China.

Abstract

Immunotherapy holds great promise for Alzheimer's disease (AD), but meningoencephalitis observed in the first AD vaccination trial, which accompanied T-lymphocytic infiltration, needs to be overcome. This study was aimed to investigate alternative approaches for a safer vaccine to treat AD. We used intramembranous fragment of amyloid-beta (IF-Abeta) to immunize Kunming mice for up to 2.5 months and then evaluated the immunization efficacy and potential adverse effects. Immunization of mice with IF-Abeta plus Freund's adjuvant resulted in moderate levels of Abeta antibodies (IgG), and the anti-sera were able to neutralize Abeta1-42-neurotoxicity in cultured primary cortical neurons. IF-Abeta itself did not show neurotoxicity, and immunization with IF-Abeta did not cause behavioral deficits in Morris water maze or any abnormalities by histological examinations of major organs including the brain. We conclude that vaccination with IF-Abeta may be a potentially safe and effective treatment for AD.
PMID: 19347579 [PubMed - indexed for MEDLINE]
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70.
CNS Neurol Disord Drug Targets. 2009 Mar;8(1):50-64.

Immunotherapy, vascular pathology, and microhemorrhages in transgenic mice.

Duke University Medical Center, Division of Neurology, Research Dr, Durham, NC 27710, USA. donna.wilcock@duke.edu

Abstract

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that results in severe cognitive decline. Amyloid plaques are a principal pathology found in AD and are composed of aggregated amyloid-beta (Abeta) peptides. According to the amyloid hypothesis, Abeta peptides initiate the other pathologies characteristic for AD including cognitive deficits. Immunotherapy against Abeta is a potential therapeutic for the treatment of humans with AD. While anti-Abeta immunotherapy has been shown to reduce amyloid burden in both mouse models and in humans, immunotherapy also exacerbates vascular pathologies. Cerebral amyloid angiopathy (CAA), that is, the accumulation of amyloid in the cerebrovasculature, is increased with immunotherapy in humans with AD and in mouse models of amyloid deposition. CAA persists in the brains of clinical trial patients that show removal of parenchymal amyloid. Mouse model studies also show that immunotherapy results in multiple small bleeds in the brain, termed microhemorrhages. The neurovascular unit is a term used to describe the cerebrovasculature and its associated cells-astrocytes, neurons, pericytes and microglia. CAA affects brain perfusion and there is now evidence that the neurovascular unit is affected in AD when CAA is present. Understanding the type of damage to the neurovascular unit caused by CAA in AD and the underlying cause of microhemorrhage after immunotherapy is essential to the success of therapeutic vaccines as a treatment for AD.
PMID: 19275636 [PubMed - indexed for MEDLINE]PMCID: PMC2659468Free PMC Article
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71.
Biochem Biophys Res Commun. 2009 Apr 24;382(1):149-52. Epub 2009 Mar 3.

Amyloid beta peptides with an additional cysteine residue can enhance immunogenicity and reduce the amyloid beta burden in an Alzheimer's disease mouse model.

Applied Research Department, Kikuchi Research Center, The Chemo-Sero-Therapeutic Research Institute, 1314-1 Kawabe, Kyokushi, Kikuchi, Kumamoto 869-1298, Japan. matsuda-ju@kaketsuken.or.jp

Abstract

For the development of a safe vaccine for Alzheimer's disease (AD), we studied the immunogenicity of amyloid beta (Abeta) peptides without adjuvant. Addition of a cysteine residue (Cys) to Abeta peptides enhanced immunogenicity in mice compared to those without Cys. Vaccination with the Abeta-Cys peptides reduced Abeta deposits in AD model mice. From these results, the Abeta-Cys peptides, administered without adjuvant, are considered candidates for vaccine therapy for AD.
PMID: 19265678 [PubMed - indexed for MEDLINE]
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72.
Biochim Biophys Acta. 2009 Jun;1790(6):566-74. Epub 2009 Mar 2.

Amyloid inhibitors enhance survival of cultured human islets.

Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.

Abstract

BACKGROUND: Amyloid fibrils created by misfolding and aggregation of proteins are a major pathological feature in a variety of degenerative diseases. Therapeutic approaches including amyloid vaccines and anti-aggregation compounds in models of amyloidosis point to an important role for amyloid in disease pathogenesis. Amyloid deposits derived from the beta-cell peptide islet amyloid polypeptide (IAPP or amylin) are a characteristic of type 2 diabetes and may contribute to loss of beta-cells in this disease.
METHODS: We developed a cellular model of rapid amyloid deposition using cultured human islets and observed a correlation between fibril accumulation and beta-cell death. A series of overlapping peptides derived from IAPP was generated.
RESULTS: A potent inhibitor (ANFLVH) of human IAPP aggregation was identified. This inhibitory peptide prevented IAPP fibril formation in vitro and in human islet cultures leading to a striking increase in islet cell viability.
CONCLUSIONS: These findings indicate an important contribution of IAPP aggregation to beta-cell death in situ and point to therapeutic applications for inhibitors of IAPP aggregation in enhancing beta-cell survival.
GENERAL SIGNIFICANCE: Anti-amyloid compounds could potentially reduce the loss of beta-cell mass in type 2 diabetes and maintain healthy human islet cultures for beta-cell replacement therapies.
PMID: 19264107 [PubMed - indexed for MEDLINE]
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73.
J Nutr Health Aging. 2009 Mar;13(3):264-7.

Development of AFFITOPE vaccines for Alzheimer's disease (AD)--from concept to clinical testing.

AFFiRiS, Viehmarktgasse 2A, A-1030 Vienna, Austria. Achim.Schneeberger@affiris.com

Abstract

Based on the notion that cerebral accumulation of certain Abeta species is central to AD pathogenesis and endowed with the knowledge that emerged during clinical testing of the first human Alzheimer vaccine, AN1792, we designed a new generation of Alzheimer vaccines. Rather than relying on full-length Abeta itself or fragments thereof, AFFITOPE vaccines use short peptides, mimicking parts of the native Abeta sequence, as their antigenic component. The technology created to identify these peptides, termed AFFITOPE-technology, at the same time provides the basis for the multi-component safety concept realized in AFFITOPE vaccines. First, as they are nonself, AFFITOPES don't need to break tolerance typically established against self proteins. This allows us to use aluminium hydroxide, the agent first approved as immunological adjuvant for human use and, thus, exhibiting an excellent safety profile. Second, AFFITOPES employed in Alzheimer vaccines are only 6 amino acids in length, which precludes the activation of Abeta-specific autoreactive T cells. Third, and above all, the AFFITOPE technology allows for controlling the specificity of the vaccine-induced antibody response focusing it exclusively on Abeta and preventing crossreactivity with APP. In a program based on two AFFITOPES allowing neoepitope targeting of Abeta (free N-terminus), this approach was taken all the way from concept to clinical application. Early clinical data support the safety concept inherent to AFFITOPE Alzheimer vaccines. Further clinical testing will focus on the identification of the optimal vaccine dose and immunization schedule. Together, result of these trials will provide a solid basis for clinical POC studies.
PMID: 19262965 [PubMed - indexed for MEDLINE]
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74.
Hum Vaccin. 2009 Jun;5(6):373-80. Epub 2009 Jun 12.

Recent advance in immunotherapies for Alzheimer disease: with special reference to DNA vaccination.

Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan.

Abstract

Alzheimer disease (AD) is the most common cause of dementia characterized by progressive neurodegeneration. Based on the amyloid cascade hypothesis, several immunotherapies for AD have been developed as curative treatment. In 1999, Schenk et al. reported for the first time that amyloid beta (Abeta) deposits in AD model mice could be reduced by active vaccination with Abeta peptide. Although clinical trials with the Abeta peptide were halted due to the development of meningoencephalitis in some treated patients, the vaccine therapy was judged to be effective on the basis of clinical and pathological analyses. Passive immunization using humanized anti-Abeta monoclonal antibodies is also under clinical trials; however they have some problems to be solved. As other strategies, DNA vaccines have been developed as immunotherapies for AD, which is simple, easily modified and can be administered without adjuvant. DNA vaccines were developed by several groups including our laboratory, which induced Abeta reduction in AD model mice without side effects. DNA vaccination may be open up new avenue of vaccine therapies for AD in the near future.
PMID: 19221518 [PubMed - indexed for MEDLINE]Free Article
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75.
Biochim Biophys Acta. 2009 Jul;1790(7):615-28. Epub 2008 Dec 29.

Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases.

Neurochemistry Laboratory, Department of Psychiatry-Neuroscience, Massachusetts General Hospital (East), Harvard Medical School, CNY2, Building 149, Charlestown, MA 02129, USA.

Abstract

Recent studies that alleles in the hemochromatosis gene may accelerate the onset of Alzheimer's disease by five years have validated interest in the model in which metals (particularly iron) accelerate disease course. Biochemical and biophysical measurements demonstrated the presence of elevated levels of neurotoxic copper zinc and iron in the brains of AD patients. Intracellular levels of APP holoprotein were shown to be modulated by iron by a mechanism that is similar to the translation control of the ferritin L- and H mRNAs by iron-responsive element (IRE) RNA stem loops in their 5' untranslated regions (5'UTRs). More recently a putative IRE-like sequence was hypothesized present in the Parkinsons's alpha synuclein (ASYN) transcript (see [A.L. Friedlich, R.E. Tanzi, J.T. Rogers, The 5'-untranslated region of Parkinson's disease alpha-synuclein messenger RNA contains a predicted iron responsive element, Mol. Psychiatry 12 (2007) 222-223. [6]]). Together with the demonstration of metal dependent translation of APP mRNA, the involvement of metals in the plaque of AD patients and of increased iron in striatal neurons in the substantia nigra (SN) of Parkinson's disease patients have stimulated the development of metal attenuating agents and iron chelators as a major new therapeutic strategy for the treatment of these neurodegenerative diseases. In the case of AD, metal based therapeutics may ultimately prove more cost effective than the use of an amyloid vaccine as the preferred anti-amyloid therapeutic strategy to ameliorate the cognitive decline of AD patients.
PMID: 19166904 [PubMed - indexed for MEDLINE]
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76.
Vaccine. 2009 Feb 25;27(9):1365-76. Epub 2009 Jan 14.

Reduced oligomeric and vascular amyloid-beta following immunization of TgCRND8 mice with an Alzheimer's DNA vaccine.

Centre for Research in Neurodegenerative Diseases, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Abstract

Immunization with amyloid-beta (Abeta) peptide reduces amyloid load in animal studies and in humans; however clinical trials resulted in the development of a pro-inflammatory cellular response to Abeta. Apoptosis has been employed to stimulate humoral and Th2-biased cellular immune responses. Thus, we sought to investigate whether immunization using a DNA vaccine encoding Abeta in conjunction with an attenuated caspase generates therapeutically effective antibodies. Plasmids encoding Abeta and an attenuated caspase were less effective in reducing amyloid pathology than those encoding Abeta alone. Moreover, use of Abeta with an Arctic mutation (E22G) as an immunogen was less effective than wild-type Abeta in terms of improvements in pathology. Low levels of IgG and IgM were generated in response to immunization with a plasmid encoding wild-type Abeta. These antibodies decreased plaque load by as much as 36+/-8% and insoluble Abeta42 levels by 56+/-3%. Clearance of Abeta was most effective when antibodies were directed against N-terminal epitopes of Abeta. Moreover, immunization reduced CAA by as much as 69+/-12% in TgCRND8 mice. Finally, high-molecular-weight oligomers and Abeta trimers were significantly reduced with immunization. Thus, immunization with a plasmid encoding Abeta alone drives an attenuated immune response that is sufficient to clear amyloid pathology in a mouse model of Alzheimer's disease.
PMID: 19150380 [PubMed - indexed for MEDLINE]
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78.
Vaccine. 2009 Feb 11;27(7):957-64. Epub 2008 Dec 27.

Antibody response and plasma Abeta1-40 levels in young Microcebus murinus primates immunized with Abeta1-42 and its derivatives.

Université Montpellier II, Montpellier F-34095, France; INSERM, U-710, Montpellier F-34095, France.

Abstract

We have been developing Abeta derivative vaccines with the objective to improve the safety of Abeta targeting immunotherapy. Our Abeta homologs are designed to have less direct toxicity and to produce a modified immune response compared to Abeta. In extensive mouse studies, all our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for studies in old primates and for human trials we assessed their effect in young lemur primates (n=25) that with age develop Abeta plaques and tau aggregates as seen in Alzheimer's disease. In the primates, all the peptides administered with alum adjuvant elicited a moderate to robust anti-Abeta IgM response. Abeta1-42, K6Abeta1-30 and K6Abeta1-30[E(18)E(19)] resulted in a high anti-Abeta IgG response, whereas Abeta1-30[E(18)E(19)] produced a weaker more variable IgG titer. Notably, 22 weeks after the 3rd immunization, IgM and IgG levels in derivative-vaccinated primates were similar to preimmune values whereas Abeta1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized Abeta1-40 often correlated with increase in Abeta1-40 in plasma, which suggests that the antibodies were binding to Abeta in vivo. Interestingly, significant transient weight gain was observed (K6Abeta1-30-, Abeta1-30[E(18)E(19)]- and Abeta1-42-treated) or a trend in the same direction (K6Abeta1-30[E(18)E(19)]-treated, adjuvant controls) following the injections. Based on these findings, we have chosen K6Abeta1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other Abeta derivatives. Our present findings indicate that most of our Abeta derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach.
PMID: 19114076 [PubMed - indexed for MEDLINE]PMCID: PMC2713060Free PMC Article
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79.
J Alzheimers Dis. 2008 Dec;15(4):555-69.

Anti-amyloid-beta immunotherapy in Alzheimer's disease: relevance of transgenic mouse studies to clinical trials.

Duke University Medical Center, Department of Medicine Division of Neurology, Durham, NC 27710, USA. donna.wilcock@duke.edu
Comment in:

Abstract

Therapeutic approaches to the treatment of Alzheimer's disease are focused primarily on the amyloid-beta peptide which aggregates to form amyloid deposits in the brain. The amyloid hypothesis states that amyloid is the precipitating factor that results in the other pathologies of Alzheimer's disease. One such therapy that has attracted significant attention is anti-amyloid-beta immunotherapy. First described in 1999, immunotherapy uses anti-amyloid-beta antibodies to lower brain amyloid levels. Active and passive immunization were shown to lower brain amyloid levels and improve cognition in multiple transgenic mouse models. Mechanisms of action were studied in these mice and revealed a complex set of mechanisms that depended on the type of antibody used. When active immunization advanced to clinical trials a subset of patients developed meningoencephalitis, an event not predicted in mouse studies. It was suspected that a T-cell response due to the type of adjuvant used was the cause. Passive immunization has also advanced to Phase III clinical trials on the basis of successful transgenic mouse studies. Reports from the active immunization clinical trial indicated that, similarly to effects observed in mouse studies, amyloid levels in brain were reduced.
PMID: 19096156 [PubMed - indexed for MEDLINE]PMCID: PMC2615484Free PMC Article
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80.
J Pharm Sci. 2009 Jun;98(6):2027-39.

Preparation, physiochemical characterization, and oral immunogenicity of Abeta(1-12), Abeta(29-40), and Abeta(1-42) loaded PLG microparticles formulations.

Bioorganic and Neurochemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu, India.

Abstract

Alzheimer's disease (AD) is caused by the deposition of beta-amyloid (Abeta) protein in brain. The current AD immunotherapy aims to prevent Abeta plaque deposition and enhance its degradation in the brain. In this work, the peptides B-cell epitope Abeta(1-12), T-cell epitope Abeta(29-40) and full-length Abeta(1-42) were loaded separately to the poly (D,L-lactide co-glycolide) (PLG) microparticles by using W/O/W double emulsion solvent evaporation method with entrapment efficacy of 70.46%, 60.93%, and 65.98%, respectively. The prepared Abeta PLG microparticles were smooth, spherical, individual, and nonporous in nature with diameters ranging from 2 to 12 microm. The cumulative in vitro release profiles of Abeta(1-12), Abeta(29-40), and Abeta(1-42) from PLG microparticles sustained for long periods and progressively reached to 73.89%, 69.29%, and 70.08% by week 15. In vitro degradation studies showed that the PLG microparticles maintained the surface integrity up to week 8 and eroded completely by week 16. Oral immunization of Abeta peptides loaded microparticles in mice elicited stronger immune response by inducing anti-Abeta antibodies for prolonged time (24 weeks). The physicochemical characterization and immunogenic potency of Abeta peptides incorporated PLG microparticles suggest that the microparticles formulation of Abeta can be a potential oral AD vaccine.
(c) 2008 Wiley-Liss, Inc.
PMID: 18980172 [PubMed - indexed for MEDLINE]
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81.
Mol Psychiatry. 2009 Mar;14(3):239-51. Epub 2008 Oct 28.

Immunization in Alzheimer's disease: naïve hope or realistic clinical potential?

The Sir James McCusker Alzheimer's Disease Research Unit, Hollywood Private Hospital, Hollywood, WA, Australia. j.foster@ecu.edu.au

Abstract

There has been considerable recent interest in vaccination of patients by immunotherapy as a potentially clinically useful methodology for combating histopathological changes in Alzheimer's disease (AD). The focus of the majority of this research has been on (1) active immunotherapy using the pre-aggregated synthetic beta-amyloid (Abeta) 42 preparation AN1792 vaccine (QS-21), or (2) passive immunization using injections of already prepared polyclonal anti-Abeta antibodies (intravenous immunoglobulin). These two clinical approaches to the treatment of patients with AD represent the focus of this review. We conclude here that, with certain caveats, immunization offers further potential as a technique for the treatment (and possible prevention) of AD. New studies are seeking to develop and apply safer vaccines that do not result in toxicity and neuroinflammation. Nevertheless, caution is warranted, and future clinical investigations are required to tackle key outstanding issues. These include the need to demonstrate efficacy in humans as well as animal models (especially with respect to the potentially toxic side effects of immunotherapy), and fine-tuning in safely guiding the immune response. The issue of defining necessary and sufficient criteria for determining clinical efficacy remains an additional important issue for future immunization trials. The vaccination methodology appears to offer substantial current promise for clearing both soluble and aggregated amyloid in AD. However, it remains to be determined whether this approach will help to repair already damaged neural systems in the disease, and the extent to which vaccination-driven amyloid clearance will impact beneficially on patients' neurocognitive capacity and their functional status. The outcomes of future studies will be important both clinically and scientifically: an important further test of the validity of the amyloid hypothesis of AD is to evaluate the impact of an effective anti-amyloid strategy on the functional status of patients with this disease.
PMID: 18957942 [PubMed - indexed for MEDLINE]
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82.
J Neuropathol Exp Neurol. 2008 Nov;67(11):1063-71.

Nonviral DNA vaccination augments microglial phagocytosis of beta-amyloid deposits as a major clearance pathway in an Alzheimer disease mouse model.

Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, Japan.

Abstract

Immunotherapies markedly reduce beta-amyloid (Abeta) burden and reverse behavioral impairment in mouse models of Alzheimer disease. We previously showed that new Abeta DNA vaccines reduced Abeta deposits in Alzheimer disease model mice without detectable side effects. Although they are effective, the mechanisms of Abeta reduction by the DNA vaccines remain to be elucidated. Here, we analyzed vaccinated and control Alzheimer disease model mice from 4 months to 15 months of age to assess which of several proposed mechanisms may underlie the beneficial effects of this vaccination. Immunohistochemical analysis revealed that activated microglial numbers increased significantly in the brains of vaccinated mice after DNA vaccination both around Abeta plaques and in areas remote from them. Microglia in treated mice phagocytosed Abeta debris more frequently than they did in untreated mice. Although microglia had an activated morphological phenotype, they did not produce significant amounts of tumor necrosis factor. Amyloid plaque immunoreactivity and Abeta concentrations in plasma increased slightly in vaccinated mice compared with controls at 9 but not at 15 months of age. Collectively, these data suggest that phagocytosis of Abeta deposits by microglia plays a central role in Abeta reduction after DNA vaccination.
PMID: 18957895 [PubMed - indexed for MEDLINE]
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83.
Brain. 2008 Dec;131(Pt 12):3299-310. Epub 2008 Oct 25.

Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain.

Division of Clinical Neurosciences, University of Southampton, Southampton General Hospital, Southampton, UK. D.Boche@soton.ac.uk

Abstract

A major feature of Alzheimer's disease is the accumulation of amyloid-beta peptide (Abeta) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of Abeta plaques can be reversed by immunotherapy. In this study, we hypothesized that Abeta in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Abeta. We have performed a follow up study of Alzheimer's disease patients immunized against Abeta42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Abeta40 and Abeta42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Abeta42 in the cerebral cortex (P<0.001) and seven times more in the leptomeninges (P = 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P = 0.001), and in the leptomeninges (P = 0.015). There was also a significantly higher level of cerebrovascular Abeta40 in the immunized cases than in the unimmunized cases (cortex: P = 0.009 and leptomeninges: P = 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular Abeta load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, Abeta is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Abeta immunization results in solubilization of plaque Abeta42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following Abeta immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined.
PMID: 18953056 [PubMed - indexed for MEDLINE]Free Article
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84.
J Neuroimmune Pharmacol. 2009 Mar;4(1):1-3.

The promise and perils of an Alzheimer disease vaccine: a video debate.

Department of Molecular Pharmacology and Physiology, School of Biomedical Sciences, College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA. scientist.dave@gmail.com

Abstract

Alzheimer's disease (AD) is a critical health care problem that has considerable social and economic impact on society. Effective treatments have been elusive. One major causal factor for the disease is believed to be the deposition of amyloid fibrils in the brain, which ultimately leads to neurodegeneration and cognitive dysfunction. Based on the amyloid hypothesis of Alzheimer's disease, many therapies presently target the amyloid beta (Abeta) peptide, the monomeric protein fragment that assembles to form fibrils. This video article takes the form of a debate between Dr. Morgan and Dr. Landreth on the merits and drawbacks of an Alzheimer's disease vaccine. Click on Supplemental Material to watch the streaming video.
PMID: 18946741 [PubMed - indexed for MEDLINE]
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87.
Nippon Rinsho. 2008 Oct;66(10):2008-12.

[Alzheimer vaccine].

[Article in Japanese]
National Institute for Longevity Sciences, NCGG.

Abstract

Autopsy cases who had received Abeta vaccine showed clearance of senile plaques, and beneficial effect was shown in patients who had high antibody titers to amyloid plaques. Thus, vaccination is widely accepted as promising therapy for Alzheimer disease. Since active immunization induced autoimmune-like meningoencephalitis, pharmaceutical companies are interested in passive immunization using monoclonal antibodies to Abeta. However, due to immunization burden and economical issues, safe active immunization is still attractive. We developed oral or nasal Abeta vaccine using viral vectors and Abeta cDNA with a signal peptide. These vaccine reduced amyloid burden and improved cognitive functions in mice. We believe this vaccine is useful for prevention and treatment of Alzheimer disease.
PMID: 18939505 [PubMed - indexed for MEDLINE]
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88.
J Neuroimmunol. 2008 Dec 15;205(1-2):57-63. Epub 2008 Oct 5.

DNA epitope vaccine containing complement component C3d enhances anti-amyloid-beta antibody production and polarizes the immune response towards a Th2 phenotype.

Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, CA 92647, United States.

Abstract

We have engineered a DNA epitope vaccine that expresses 3 self-B cell epitopes of Abeta(42) (3Abeta(1-11)), a non-self T helper (Th) cell epitope (PADRE), and 3 copies of C3d (3C3d), a component of complement as a molecular adjuvant, designed to safely reduce CNS Abeta. Immunization of mice with 3Abeta(1-11)-PADRE epitope vaccine alone generated only moderate levels of anti-Abeta antibodies and a pro-inflammatory T helper (Th1 phenotype) cellular immune response. However, the addition of 3C3d to the vaccine construct significantly augmented the anti-Abeta humoral immune response and, importantly, shifted the cellular immune response towards the potentially safer anti-inflammatory Th2 phenotype.
PMID: 18838175 [PubMed - indexed for MEDLINE]PMCID: PMC2637203Free PMC Article
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89.
Neuropsychiatr. 2008;22(3):153-71.

[Therapy of Alzheimer's disease: current status and future development].

[Article in German]
Universitätsklinik für Neurologie, Medizinische Universität Graz. reinhold.schmidt@meduni-graz.at

Abstract

Cholinesterase inhibitors and memantine can slow the course of Alzheimer's disease. In Austria the frequency of treatment is in the upper third among countries of the EU. Yet, the majority of Alzheimer patients does not receive adequate medication. Compliance to treatment is low. Studies on cholinesterase inhibitors show that only one third and one fifth of patients adhere to medication after 3 months and 12 months, respectively. Causes for low compliance are only partly patient-related, many factors are system-inherent. Knowledge of these factors is a pre-requisite for the treating physician to improve current unfavourable situation. Present treatment strategies are symptomatic, causal disease-modifying therapies are urgently needed. Research activity in the field is high and dominated by the amyloid hypothesis. We here review the basis and recent studies on secretase-inhibitors, immunization, aggregation of Abeta, statins and PPARgamma-agonists. Research towards strategies against tau-pathology is less dominant and focuses on inhibition of kinases and increase of activity of phosphatases. Causal therapies would have great effects on a population basis even if efficacy is only moderate. A disease-modifying therapy which delays the onset of Alzheimer disease by 5 years, will probably reduce the number of patients by nearly 50% during the next 50 years.
PMID: 18826870 [PubMed - indexed for MEDLINE]
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90.
J Neuroinflammation. 2008 Sep 29;5:42.

Mannan-Abeta28 conjugate prevents Abeta-plaque deposition, but increases microhemorrhages in the brains of vaccinated Tg2576 (APPsw) mice.

The Institute for Brain Aging and Dementia, University of California Irvine, Irvine, CA 92697-4540, USA. ipetrush@uci.edu

Abstract

BACKGROUND: New pre-clinical trials in AD mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse responses that occurred during the clinical trials with AN-1792 vaccine formulation. Recently, we have pursued an alternative immunization strategy that replaces QS21 the Th1 type adjuvant used in the AN-1792 clinical trial with a molecular adjuvant, mannan that can promote a Th2-polarized immune response through interactions with mannose-binding and CD35/CD21 receptors of the innate immune system. Previously we established that immunization of wild-type mice with mannan-Abeta28 conjugate promoted Th2-mediated humoral and cellular immune responses. In the current study, we tested the efficacy of this vaccine configuration in amyloid precursor protein (APP) transgenic mice (Tg2576).
METHODS: Mannan was purified, activated and chemically conjugated to Abeta28 peptide. Humoral immune responses induced by the immunization of mice with mannan-Abeta28 conjugate were analyzed using a standard ELISA. Abeta42 and Abeta40 amyloid burden, cerebral amyloid angiopathy (CAA), astrocytosis, and microgliosis in the brain of immunized and control mice were detected using immunohistochemistry. Additionally, cored plaques and cerebral vascular microhemorrhages in the brains of vaccinated mice were detected by standard histochemistry.
RESULTS: Immunizations with low doses of mannan-Abeta28 induced potent and long-lasting anti-Abeta humoral responses in Tg2576 mice. Even 11 months after the last injection, the immunized mice were still producing low levels of anti-Abeta antibodies, predominantly of the IgG1 isotype, indicative of a Th2 immune response. Vaccination with mannan-Abeta28 prevented Abeta plaque deposition, but unexpectedly increased the level of microhemorrhages in the brains of aged immunized mice compared to two groups of control animals of the same age either injected with molecular adjuvant fused with an irrelevant antigen, BSA (mannan-BSA) or non-immunized mice. Of note, mice immunized with mannan-Abeta28 showed a trend toward elevated levels of CAA in the neocortex and in the leptomeninges compared to that in mice of both control groups.
CONCLUSION: Mannan conjugated to Abeta28 provided sufficient adjuvant activity to induce potent anti-Abeta antibodies in APP transgenic mice, which have been shown to be hyporesponsive to immunization with Abeta self-antigen. However, in old Tg2576 mice there were increased levels of cerebral microhemorrhages in mannan-Abeta28 immunized mice. This effect was likely unrelated to the anti-mannan antibodies induced by the immunoconjugate, because control mice immunized with mannan-BSA also induced antibodies specific to mannan, but did not have increased levels of cerebral microhemorrhages compared with non-immunized mice. Whether these anti-mannan antibodies increased the permeability of the blood brain barrier thus allowing elevated levels of anti-Abeta antibodies entry into cerebral perivascular or brain parenchymal spaces and contributed to the increased incidence of microhemorrhages remains to be investigated in the future studies.
PMID: 18823564 [PubMed - indexed for MEDLINE]PMCID: PMC2567310Free PMC Article
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91.
J Immunoassay Immunochem. 2008;29(4):332-47.

Complexities of clinical assay development and optimization prior to first-in-man immunization trials - a description of immunogenicity assay development for the testing of samples from a phase 1 Alzheimer's vaccine trial.

Vaccine and Biologics Research, Merck Research Labs, Wayne, PA 19087, USA.

Abstract

Immunogenicity is often a critical clinical endpoint in the assessment of vaccines prior to the submission of data to regulatory agencies. As a result, the assays used to measure immunogenicity must be highly characterized, well-controlled, and statistically supported. These goals are not easily attained, however, when the development of the assay must occur prior to the first-in-man studies. Two significant barriers exist in the development of these assays: (1) the lack of experience with the performance of a novel antigen in a clinical assay, and (2) the lack of available proper human clinical samples to create reference standards and assess sample matrices. To help to overcome these obstacles, we employed a screening experimental design to assess assay optimization. Design of experiments (DOE) is a statistical tool that allows for the evaluation of all of the key assay parameters to determine the optimal conditions for the assay, as well as determine if there are any interactions of these parameters on the response of the assay. The multivariate approach that is integral to DOE helps to overcome the lack of experience with the assay reagents by facilitating an understanding of how the variables work together in the performance of the assay. Here, we outline the use of full and fractional factorial DOE in the optimization of a clinical assay on two platforms, Luminex and ELISA, for the measurement of antibodies to the beta-amyloid peptide (Abeta) for a novel first-in-man vaccine program. Both platforms are evaluated in an attempt to determine the assay best suited to the needs of the program. We also describe the specificity experiments performed to further characterize the utility of each assay platform.
PMID: 18821408 [PubMed - indexed for MEDLINE]
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92.
Bull Acad Natl Med. 2008 Feb;192(2):363-78; discussion 378-80.

[Alzheimer's disease: from brain lesions to new drugs].

[Article in French]
Université Paris V, Hôpital Broca, Fondation nationale de Gérontologie, International Longevity Center (ILC)-France.

Abstract

We review the main therapeutic targets in Alzheimer's disease. Current treatments include cholinesterase inhibitors and the glutamate-modulating drug memantin. Other neurotransmitters such as serotonin, histamine and noradrenaline may also be targeted. Although useful, however, these symptomatic treatments do not prevent neuronal degeneration and death. Epidemiological studies suggest that treatments given for other reasons, such as antiinflammatory agents (including NSAIDs), cholesterol-lowering drugs, hormone replacement therapy and antioxidants, may prevent or improve Alzheimer-type dementia, but this is not always borne out in controlled clinical trials. Prevention of hypertension significantly reduces the incidence of vascular dementia and of Alzheimer-type dementia, albeit through an unknown mechanism. Alzheimer's disease is characterized by two main lesions: amyloid plaques and neurofibrillary tangles composed of aggregated A Beta peptides and hyperphosphorylated tau. Active and passive immunization against A beta has given promising results. Other exciting approaches include modulation of A beta processing by inhibiting BACE1 or gamma-secretase or upregulating alpha-secretase; A beta peptide catabolism; inhibition of beta fibrillization; and reducing tau phosphorylation or inhibiting tau aggregation. More remote possibilities include gene therapy and the use of growth factors to increase neurogenesis.
PMID: 18819689 [PubMed - indexed for MEDLINE]
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93.
Bull Acad Natl Med. 2008 Feb;192(2):333-42; discussion 343-4.

[Alzheimer's disease: therapeutic perspectives].

[Article in French]
Centre des Maladies Cognitives et Comportementales et Inserm U 610, Hôpital de la Salpêtrière, 47, boulevard de l'Hôpital, 75013 Paris.

Abstract

Current treatments for Alzheimer's disease aim to compensate for biochemical deficits in the brain. They are purely symptomatic and restore the central cholinergic deficit. Acetylcholinesterase inhibitors have modest but significant efficacy on cognitive disorders, activities of daily living, and the global clinical impression. Glutaminergic receptor antagonists are used for more advanced forms. Future treatments may be curative, acting specifically on the amyloid cascade. Secretase inhibitors and immunotherapy are in the pipeline. Trials will begin within a few months and will open up new perspectives.
PMID: 18819687 [PubMed - indexed for MEDLINE]
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94.
Bull Acad Natl Med. 2008 Feb;192(2):303-18; discussion 318-21.

[The lesions of Alzheimer's disease: which therapeutic perspectives?].

[Article in French]
Laboratoire de Neuropathologie Raymond Escourolle, Groupe Hospitalier Pitié-Salpêtrière, 75651 Paris. charles.duyckaerts@psl.aphp.fr

Abstract

The brain lesions associated with Alzheimer's disease are caused by extracellular accumulation of Abeta peptide and intracellular accumulation of tau protein. Abeta peptide makes the core of the senile plaque (the "focal deposit"); it is also present in the extracellular "diffuse deposits" and in the vessel walls. Neurofibrillary tangles, and neuropil threads are composed of hyperphosphorylated tau that also accumulates in the processes of the corona of the senile plaque. The Abeta deposits first involve the neocortex, while the tau pathology is initially found in the hippocampal region. Abeta deposits first occur in the neocortex, while intracellular tau accumulation mainly affect the hippocampal region. Abeta peptide deposits are initially found in all the neocortical areas, then involve the hippocampus and the subcortical nuclei. Tau lesions successively involve the hippocampal regions, multi- and uni-modal areas and finally the primary cortices in stereotyped stages. Mutations of APP, the precursor of Abeta peptide, cause autosomal dominant familial Alzheimer disease, suggesting that a cascade of reactions link Abeta overproduction, tau pathology and the clinical phenotype. Transgenic mice bearing the mutated human APP gene (APP mice) develop A deposits. Systemic injection of Abeta peptide prevents the deposition of Abeta peptide. However, a clinical trial had to be interrupted when meningoencephalitis occurred in a significant proportion of treated patients. Post mortem studies showed a relative scarcity of Abeta deposits. Forthcoming immunotherapy studies should soon show whether the prevention of Abeta deposition interrupts disease progression.
PMID: 18819685 [PubMed - indexed for MEDLINE]
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95.
Brain Nerve. 2008 Aug;60(8):931-40.

[Novel vaccine therapy for Alzheimer's disease--recent progress and our approach].

[Article in Japanese]
Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183 8526, Japan.

Abstract

Alzheimer's disease (AD) is the most common cause of dementia with very few drugs available for its treatment. In 1999, Schenk et al reported that Abeta 1-42 peptide vaccination in AD model mice causes the reduction in Abeta deposits. Thereafter, a vaccine therapy was developed for the curative treatment of AD. Clinical trials of active vaccination for AD patients were halted due to the development of meningoencephalitis in some patients; however, vaccine therapy is thought to be effective based on the clinical and pathological findings of the vaccinated patients. Based on this information, active and passive vaccines have been developed, some of which are now urdergoing clinical trials in Europe and USA. However, there are still some problems for general application of such drugs for AD patients. Recently, we developed nonviral DNA vaccines and used them to obtain a substantial Abeta reduction in AD model mice without any side effects. In this article, we will review conventional vaccine therapies and introduce our non-viral DNA vaccine therapy. Finally, we will present data regarding the mechanisms of Abeta reduction after DNA vaccination. DNA vaccination for AD may open up new avenues in vaccine therapy for the treatment of AD.
PMID: 18717197 [PubMed - indexed for MEDLINE]
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96.
Sci China C Life Sci. 2008 Aug;51(8):743-50. Epub 2008 Aug 3.

Prevention of pathological change and cognitive degeneration of Tg2576 mice by inoculating Abeta(1-15) vaccine.

Department of Anatomy, Medical College of Shanghai Jiao Tong University, Shanghai 200025, China.

Abstract

This study aims to discuss the effect of preventing pathological changes and cognitive degeneration of Tg2576 mice by inoculating the subunit fragment of Abeta vaccine. Thirty-two Tg2576 mice were randomly divided into four groups, each having eight mice: Group I, the control group, inoculated with adjuvants; Group II, the Abeta(42) group, inoculated with Abeta(42) vaccine; Group III, the Abeta(1-15) group, inoculated with Abeta(1-15) vaccine; and Group IV, the Abeta(36-42) group, inoculated with Abeta(36-42) vaccine. The titer of the serum antibody against Abeta(42) (Group II) was significantly higher than that of the control group (Group I), and a low level of antibodies could be detected in the brain homogenate in the three vaccine-inoculated groups. Morris water maze test showed that the Abeta(42) group, Abeta(1-15) group and Abeta(36-42) group were obviously improved compared with the control group. The cultured splenocytes sampled from each group were induced by Con A or their respective antigens, and the cell proliferation of the three vaccine-inoculated groups was significantly higher than that of the control group. In the Abeta(42) group, IL2 and IFN-gamma were relatively low and IL4 and IL10 were relatively high. By contrast, IL4 and IL10 were much higher in the Abeta(1-15) group and IL2 and IFN-gamma were much higher in the Abeta(36-42) group. The immunohistochemical test showed a large number of senile plaques in the brain cortex and hippocampus of the mice in the control group, no senile plaque in the brain of the Abeta(1-15) group and Abeta(42) group mice, and a small number of senile plaques in the brain of the Abeta(36-42) group mice. The results suggest that the subunit fragment of Abeta(1-15) vaccine could prevent not only cognitive and behavioral degeneration but also Abeta deposition and formation of senile plaques in Tg2576 mice.
PMID: 18677602 [PubMed - indexed for MEDLINE]
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97.
Lancet Neurol. 2008 Sep;7(9):805-11. Epub 2008 Jul 28.

Amyloid-beta immunisation for Alzheimer's disease.

Department of Neurology, New York University School of Medicine, New York, NY 10016, USA. thomas.wisniewski@nyumc.org

Abstract

Alzheimer's disease is the main cause of dementia in elderly people and is becoming an ever greater problem as societies worldwide age. Treatments that stop or at least effectively modify disease course do not yet exist. In Alzheimer's disease, the conversion of the amyloid-beta peptide (Abeta) from a physiological water-soluble monomeric form into neurotoxic oligomeric and fibrillar forms rich in stable beta-sheet conformations is an important event. The most toxic forms of Abeta are thought to be oligomers, and dimers might be the smallest neurotoxic species. Numerous immunological approaches that prevent the conversion of the normal precursor protein into pathological forms or that accelerate clearance are in development. More than ten new approaches to active and passive immunotherapy are under investigation in clinical trials with the aim of producing safe methods for immunological therapy and prevention. A delicate balance between immunological clearance of an endogenous protein with acquired toxic properties and the induction of an autoimmune reaction must be found.
PMID: 18667360 [PubMed - indexed for MEDLINE]PMCID: PMC2752661Free PMC Article
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99.
J Neuroimmunol. 2008 Aug 30;200(1-2):1-10. Epub 2008 Jul 22.

Mutant amyloid-beta-sensitized dendritic cells as Alzheimer's disease vaccine.

Johnnie B. Byrd, Sr., Alzheimer's Center and Research Institute, 4001 East Fletcher Avenue, Tampa, FL 33613, United States. ccao@byrdinstitute.org

Abstract

Vaccines using bone marrow-derived dendritic cells (DCs) sensitized to Abeta 1-42 peptide and other mutant peptides were tested on BALB/c and APP(SW) transgenic mice. Wild type Abeta 1-42-sensitized DC vaccine (DCSV) produced no response, but all peptides with a T-cell epitope mutation induced antibody responses without inflammation. DCSV with Abeta 1-25 peptide with mutated T-cell epitope failed to induce antibody response, while DCSV with Abeta 1-35 with mutated T-cell epitope produced a strong antibody response. The entire T-cell epitope is required in a DC vaccine to induce antibody response. DCSV with Abeta peptide carrying the entire mutant T-cell epitope may be an appropriate vaccine against AD.
PMID: 18649951 [PubMed - indexed for MEDLINE]
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100.
Biotechnol Lett. 2008 Oct;30(10):1839-45. Epub 2008 Jul 5.

Transgenic tomatoes expressing human beta-amyloid for use as a vaccine against Alzheimer's disease.

Plant Genomics Research Center, KRIBB, 111 Gwahangno, Yuseong-gu, Daejeon 305-806, Korea.

Abstract

Human beta-amyloid (Abeta) is believed to be one of the main components of Alzheimer's disease, so reduction of Abeta is considered a key therapeutic target. Using Agrobacterium-mediated nuclear transformation, we generated transgenic tomatoes for Abeta with tandem repeats. Integration of the human Abeta gene into the tomato genome and its transcription were detected by PCR and Northern blot, respectively. Expression of the Abeta protein was confirmed by western blot and ELISA, and then the transgenic tomato line expressing the highest protein level was selected for vaccination. Mice immunized orally with total soluble extracts from the transgenic tomato plants elicited an immune response after receiving a booster. The results indicate that tomato plants may provide a useful system for the production of human Abeta antigen.
PMID: 18604480 [PubMed - indexed for MEDLINE]PMCID: PMC2522325Free PMC Article
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