Int J Alzheimers Dis. 2010 Aug 12;2010. pii: 723782.
Neuron loss in transgenic mouse models of Alzheimer's disease.
Division of Molecular Psychiatry and Alzheimer Ph.D. Graduate School, Department of Psychiatry, University of Goettingen, von-Siebold-Str. 5, 37075 Goettingen, Germany.
Abstract
Since their initial generation in the mid 1990s, transgenic mouse models of Alzheimers's disease (AD) have been proven to be valuable model systems which are indispensable for modern AD research. Whereas most of these models are characterized by extensive amyloid plaque pathology, inflammatory changes and often behavioral deficits, modeling of neuron loss was much less successful. The present paper discusses the current achievements of modeling neuron loss in transgenic mouse models based on APP/Aβ and Tau overexpression and provides an overview of currently available AD mouse models showing these pathological alterations.PMID: 20871861 [PubMed - in process]PMCID: PMC2943100Free PMC Article
Related citations
22.
Free Radic Biol Med. 2010 Sep 22. [Epub ahead of print]
Oxidative Modification to LDL-related Receptor Protein 1 (LRP1) in Hippocampus from Subjects with Alzheimer's Disease: Implications for Aβ Accumulation in AD Brain.
Department of Chemistry, University of Kentucky, Lexington KY 40506-0055; Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506-0059, USA.
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized histopathologically by the presence of senile plaques (SP), neurofibrillary tangles, and synapse loss. The main component of SP is amyloid-β peptide (Aβ) that has been associated with increased oxidative stress, leading to oxidative modification of proteins and consequently to neurotoxicity and neurodegeneration. Low-density lipoprotein receptor-related protein 1 (LRP1) is the primary moiety responsible for the efflux of Aβ from the brain to the blood across the blood-brain barrier (BBB). Impaired brain-to-blood transport of Aβ by LRP1 has been hypothesized to contribute to increased levels of Aβ in AD brain. The cause of LRP1 dysfunction is unknown, but we have hypothesized that Aβ oxidizes LRP1, thus damaging its own transporter. Consistent with this notion, we report in the current study a significant increase in the levels of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) bound to transmembrane LRP1 in AD hippocampus. In contrast, the levels of LRP1-resident 3-nitrotyrosine (3NT) did not show a significant increase in AD hippocampus compared to age-matched controls. Based on this study, we propose that Aβ impairs its own efflux from the brain by oxidation of its transporter LRP1, leading to increased Aβ deposition in brain, thereby contributing to subsequent cognitive impairment in AD.PMID: 20869432 [PubMed - as supplied by publisher]
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23.
Neurosci Lett. 2010 Sep 30. [Epub ahead of print]
Cholinesterase inhibitor use is associated with increased plasma levels of anti-Abeta 1-42 antibodies in Alzheimer's disease patients.
Conti E, Galimberti G, Tremolizzo L, Masetto A, Cereda D, Zanchi C, Piazza F, Casati M, Isella V, Appollonio I, Ferrarese C.
Department of Neuroscience and Biomedical Technologies, University of Milano-Bicocca, San Gerardo Hospital, Via Cadore 48, 20052 Monza (MI), Italy.
Abstract
Acetyl-cholinesterase inhibitors (AChEI) are drugs frequently prescribed for the treatment of Alzheimer's disease (AD), exerting an effect on cognition, as well as on behavioural and psychological symptoms of dementia and activities of daily living. The efficacy of AChEI may be ascribed not only to the activation of cholinergic transmission, but also to other mechanisms, among which a putative regulation of the immune response has already been hypothesized. In the present study, we evaluated, in a cross-sectional sample of 66AD patients and 48 healthy controls, the putative influence of AChEI on anti-Abeta 1-42 antibody plasma levels by ELISA assay. AD patients receiving AChEI therapy showed increased plasma levels of anti-Abeta 1-42 antibodies respect to untreated AD patients and antibodies levels similar to those of healthy controls, both before and after normalization by total IgG values. Our results support a potential role of AChEI in the modulation of the immune response against Abeta. We suggest that a strategy aimed at increasing the endogenous response against this peptide might represent an interesting therapeutic target to be further investigated.PMID: 20869427 [PubMed - as supplied by publisher]
Related citations 24.
Biochimie. 2010 Sep 22. [Epub ahead of print]
Targeting cyclooxygenases-1 and -2 in neuroinflammation: Therapeutic implications.
Molecular Neuroscience Unit, Brain Physiology and Metabolism Section, National Institute on Aging, NIH, 9 Memorial Drive, Bldg 9 Room 1S126, Bethesda, MD 20892, USA.
Abstract
Neuroinflammation has been implicated in the pathogenesis or the progression of a variety of acute and chronic neurological and neurodegenerative disorders, including Alzheimer's disease. Prostaglandin H synthases or cyclooxygenases (COX -1 and COX-2) play a central role in the inflammatory cascade by converting arachidonic acid into bioactive prostanoids. In this review, we highlighted recent experimental data that challenge the classical view that the inducible isoform COX-2 is the most appropriate target to treat neuroinflammation. First, we discussed data showing that COX-2 activity is linked to anti-inflammatory and neuroprotective actions and is involved in the generation of novel lipid mediators with pro-resolution properties. Then, we reviewed recent data demonstrating that COX-1, classically viewed as the homeostatic isoform, is actively involved in brain injury induced by pro-inflammatory stimuli including Aβ, lipopolysaccharide, IL-1β, and TNF-α. Overall, we suggest revisiting the traditional views on the roles of each COX during neuroinflammation and we propose COX-1 inhibition as a viable therapeutic approach to treat CNS diseases with a marked inflammatory component.PMID: 20868723 [PubMed - as supplied by publisher]
Related citations 25.
Eur J Pharmacol. 2010 Sep 22. [Epub ahead of print]
Puerarin attenuates amyloid-beta-induced cognitive impairment through suppression of apoptosis in rat hippocampus in vivo.
Abstract
Elevated levels of β-amyloid (Aβ) in the brains being a hallmark of Alzheimer's disease have been believed to play a critical role in the cognitive dysfunction that occurs in Alzheimer's disease. Recent evidence suggests that Aβ induces neuronal apoptosis in the brain and in primary neuronal cultures. In this study, we investigated the effects of puerarin, a phytoestrogen isolated from Pueraria lobata, on cognitive function and neuronal apoptosis in the intrahippocampal injection of Aβ rats and its mechanism of action. The results show the intrahippocampal injection of Aβ induced a spatial memory deficit, apoptosis, and caspase-9 activation in hippocampal neurons. Puerarin treatment ameliorated Aβ(1-42)-induced cognitive impairment and reversed the increase of apoptosis in the hippocampus. The attenuation is associated with the activation of Akt and phosphorylation of Bad. These results suggest that puerarin may be an anti-Alzheimer's disease candidate drug to suppress both Alzheimer's disease-related neuronal cell apoptosis and dysfunction of the memory system.PMID: 20868658 [PubMed - as supplied by publisher]
Related citations 26.
Hippocampus. 2010 Apr 13. [Epub ahead of print]
Chronic psychosocial stress accelerates impairment of long-term memory and late-phase long-term potentiation in an at-risk model of Alzheimer's disease.
Department of Pharmacological and Pharmaceutical Sciences, University of Houston, College of Pharmacy, Houston, Texas.
Abstract
Although it is generally agreed that Aβ contributes to the pathogenesis of AD, its precise role in AD and the reason for the varying intensity and time of onset of the disease have not been elucidated. In addition to genetic factors, environmental issues such as stress may also play a critical role in the etiology of AD. This study examined the effect of chronic psychosocial stress in an at-risk (treatment with a subpathogenic dose of Aβ; "subAβ") rat model of AD on long-term memory by three techniques: memory tests in the radial arm water maze, electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of learning- and long-term memory-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAβ rat model of AD was induced by continuous infusion of 160 pmol/day Aβ(1-42) via a 14-day i.c.v. osmotic pump. All tests showed that subAβ rats were not different from control rats. Result from behavioral tests and electrophysiological recordings showed that infusion of subAβ in chronically stressed rats (stress/subAβ group) caused significant impairment of cognitive functions and late-phase long-term potentiation (L-LTP). Molecular analysis of various signaling molecules after expression of L-LTP, revealed an increase in the levels of p-CREB in control, stress, and subAβ rats, but not in the stress/subAβ rats. These findings suggest that the chronic stress-induced molecular alteration may accelerate the impairment of cognition and synaptic plasticity in individuals "at-risk" for AD. © 2010 Wiley-Liss, Inc.PMID: 20865724 [PubMed - as supplied by publisher]
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27.
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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28.
Am J Pathol. 2010 Sep 23. [Epub ahead of print]
CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models.
From the Department of Neurosciences, Lerner Research Institute,* The Cleveland Clinic; and the Departments of Neurosciences, and Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio.
Abstract
Microglia, the primary immune effector cells in the brain, continually monitor the tissue parenchyma for pathological alterations and become activated in Alzheimer's disease. Loss of signaling between neurons and microglia via deletion of the microglial receptor, CX3CR1, worsens phenotypes in various models of neurodegenerative diseases. In contrast, CX3CR1 deficiency ameliorates pathology in murine stroke models. To examine the role of CX3CR1 in Alzheimer's disease-related β-amyloid pathology, we generated APPPS1 and R1.40 transgenic mouse models of Alzheimer's disease deficient for CX3CR1. Surprisingly, CX3CR1 deficiency resulted in a gene dose-dependent reduction in β-amyloid deposition in both the APPPS1 and R1.40 mouse models of AD. Immunohistochemical analysis revealed reduced staining for CD68, a marker of microglial activation. Furthermore, quantitative immunohistochemical analysis revealed reduced numbers of microglia surrounding β-amyloid deposits in the CX3CR1-deficient APPPS1 animals. The reduced β-amyloid pathology correlated with reduced levels of TNFα and CCL2 mRNAs, but elevated IL1β mRNA levels, suggesting an altered neuroinflammatory milieu. Finally, to account for these seemingly disparate results, both in vitro and in vivo studies provided evidence that CX3CL1/CX3CR1 signaling alters the phagocytic capacity of microglia, including the uptake of Aβ fibrils. Taken together, these results demonstrate that loss of neuron-microglial fractalkine signaling leads to reduced β-amyloid deposition in mouse models of AD that is potentially mediated by altered activation and phagocytic capability of CX3CR1-deficient microglia.PMID: 20864679 [PubMed - as supplied by publisher]
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29.
J Biol Chem. 2010 Sep 23. [Epub ahead of print]
Macroautophagy is not directly involved in the metabolism of amyloid precursor protein.
University College Dublin, Ireland;
Abstract
Alterations in the metabolism of amyloid precursor protein (APP) are believed to play a central role in Alzheimers disease (AD) pathogenesis. Burgeoning data indicates that APP is proteolytically processed in endosomal-autophagic-lysosomal (EAL) compartments. In this study, we used both in vivo and in vitro paradigms to determine if alterations in macroautophagy affect APP metabolism. Three mouse models of glycosphingolipid (GSL) storage diseases, namely, Niemann Pick Type C1, GM1 gangliosidosis and Sandhoff disease had mTOR-independent increases in the autophagic vacuole (AV) associated protein, LC3-II, indicative of impaired lysosomal flux. APP-C-terminal fragments (APP-CTFs) were also increased in brains of the three mouse models, however, discrepancies between LC3-II and APP-CTFs were seen between primary (GM1 gangliosidosis and Sandhoff disease) and secondary (Niemann Pick Type C1) lysosomal storage models. APP-CTFs were proportionately higher than LC3-II in cerebellar regions of GM1 gangliosidosis and Sandhoff disease, while LC3-II increased before APP-CTFs in brains of NPC1 mice. Endogenous murine Aβ40 from RIPA-soluble extracts was increased in brains of all three mice. The in vivo relationship between AV and APP-CTF accumulation was also seen in cultured neurons treated with agents that impair primary (chloroquine, leupeptin + pepstatin) and secondary (U18666A, vinblastine) lysosomal flux. However, Aβ secretion was unaffected by agents that induced autophagy (rapamycin) or impaired AV clearance, and LC3-II positive AVs predominantly co-localised with degradative LAMP-1-positive lysosomes. These data suggest that neuronal macroautophagy does not directly regulate APP metabolism, but highlights the important anti-amyloidogenic role of lysosomal proteolysis in post-secretase APP-CTF catabolism.PMID: 20864542 [PubMed - as supplied by publisher]
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30.
J Pharmacol Exp Ther. 2010 Sep 23. [Epub ahead of print]
H3 Receptor Miniseries: H3 Receptors and Pain Modulation: Peripheral, Spinal and Brain Interactions.
1 Albany Medical College MC-136;
Abstract
Histamine H(3) receptors (H(3)Rs), distributed within in the brain, the spinal cord, and on specific types of primary sensory neurons, can modulate pain transmission by several mechanisms. In the skin, H(3)Rs are found on certain Aβ fibers, and on keratinocytes and Merkel cells, as well as on deep dermal, peptidergic Aδ fibers terminating on deep dermal blood vessels. Activation of H(3)Rs on the latter in the skin, heart, lung and dura mater reduces CGRP and substance P release, leading to anti-inflammatory (but not antinociceptive) actions. However, activation of H(3)Rs on the spinal terminals of these sensory fibers reduces nociceptive responding to low intensity mechanical stimuli, and to inflammatory stimuli such as formalin. These findings suggest that H(3)R agonists might be useful analgesics, but these drugs have not been tested in clinically-relevant pain models. Paradoxically, H(3) antagonists/ inverse agonists have also been reported to attenuate several types of pain responses, including phase II responses to formalin. In the periaquaductal gray (PAG, an important pain regulatory center), the H(3) inverse agonist thioperamide releases neuronal histamine and mimics histamine's biphasic modulatory effects in thermal nociceptive tests. Newer H(3) inverse agonists with potent, selective, and brain-penetrating properties show efficacy in several neuropathic and arthritis pain models, but the sites and mechanisms for these actions remain poorly understood.PMID: 20864501 [PubMed - as supplied by publisher]
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31.
J Neuroimmunol. 2010 Sep 21. [Epub ahead of print]
Anti-11[E]-pyroglutamate-modified amyloid β antibodies cross-react with other pathological Aβ species: Relevance for immunotherapy.
Perez-Garmendia R, Ibarra-Bracamontes V, Vasilevko V, Luna-Muñoz J, Mena R, Govezensky T, Acero G, Manoutcharian K, Cribbs DH, Gevorkian G.
Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), AP 70228, Cuidad Universitaria, México DF, 04510, 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.PMID: 20864186 [PubMed - as supplied by publisher]
Related citations 32.
J Neurol Sci. 2010 Sep 20. [Epub ahead of print]
Oxidative stress in Alzheimer's disease hippocampus: A topographical study.
Institute of Neurological and Gerontological Sciences, Faculty of Medicine, International University of Catalonia, Josep Trueta, s/n. 08195 Sant Cugat del Vallès, Barcelona, Spain.
Abstract
Advanced glycation end-products (AGEs) and their receptor (RAGE) are molecules related to oxidative stress demonstrated in aging and in several pathological disorders including Alzheimer's disease (AD). Aging has been considered the main risk factor for AD. Amyloid deposits (Aβ-D) and neurofibrillary tangles (NFT) are pathological changes related to AD involving hippocampal regions. Different degrees of AD pathology have been described according to distribution of NFTs in different topographical regions of hippocampus and cerebral cortex. The hippocampus shows a selective vulnerability under several noxes especially those including hypoxia. Hypoxia in the nervous tissue induces oxidative stress. In an attempt to find out more about anatomical distribution of the oxidative stress through hippocampal regions in AD, a collection of brains were studied. Samples from deceased patients who had suffered from AD and from age-matched controls were immunohistochemically studied with AGE and RAGE antibodies according to a topographical division of the hippocampus and brain cortical regions. Results suggest that an oxidative stress pathway starts in the CA3 sector progresses to CA1 and then continues to other hippocampal and cortical areas building a pathoclitic pathway for Alzheimer's disease progression.PMID: 20863531 [PubMed - as supplied by publisher]
Related citations 33.
Int J Alzheimers Dis. 2010 Sep 2;2010. pii: 417314.
Pathological Hallmarks, Clinical Parallels, and Value for Drug Testing in Alzheimer's Disease of the APP[V717I] London Transgenic Mouse Model.
Tanghe A, Termont A, Merchiers P, Schilling S, Demuth HU, Scrocchi L, Van Leuven F, Griffioen G, Van Dooren T.
reMYND NV, Gaston Geenslaan 1, 3001 Heverlee-Leuven, Belgium.
Abstract
The APP[V717I] London (APP-Ld) mouse model recapitulates important pathological and clinical hallmarks of Alzheimer's disease (AD) and is therefore a valuable paradigm for evaluating therapeutic candidates. Historically, both the parenchymal and vascular amyloid deposits, and more recently, truncated and pyroglutamate-modified Abeta(3(pE)-42) species, are perceived as important hallmarks of AD-pathology. Late stage symptoms are preceded by robust deficits in orientation and memory that correlate in time with Abeta oligomerization and GSK3β-mediated phosphorylation of endogenous murine Tau, all markers that have gained considerable interest during the last decade. Clinical parallels with AD patients and the value of the APP-Ld transgenic mouse model for preclinical in vivo testing of candidate drugs are discussed.PMID: 20862386 [PubMed - in process]PMCID: PMC2939388
Related citations 34.
Int J Alzheimers Dis. 2010 Aug 24;2010. pii: 761571.
Combined Analysis of CSF Tau, Aβ42, Aβ1-42% and Aβ1-40% in Alzheimer's Disease, Dementia with Lewy Bodies and Parkinson's Disease Dementia.
Department of Psychiatry, Psychotherapy and Addiction Medicine, Kliniken Essen-Mitte, University of Duisburg-Essen, Henricistrasse 92, 45136 Essen, Germany.
Abstract
We studied the diagnostic value of CSF Aβ42/tau versus low Aβ1-42% and high Aβ1-40(ox)% levels for differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), respectively. CSF of 45 patients with AD, 15 with DLB, 21 with Parkinson's disease dementia (PDD), and 40 nondemented disease controls (NDC) was analyzed by Aβ-SDS-PAGE/immunoblot and ELISAs (Aβ42 and tau). Aβ42/tau lacked specificity in discriminating AD from DLB and PDD. Best discriminating biomarkers were Aβ1-42% and Aβ1-40(ox)% for AD and DLB, respectively. AD and DLB could be differentiated by both Aβ1-42% and Aβ1-40(ox)% with an accuracy of 80% at minimum. Thus, we consider Aβ1-42% and Aβ1-40(ox)% to be useful biomarkers for AD and DLB, respectively. We propose further studies on the integration of Aβ1-42% and Aβ1-40(ox)% into conventional assay formats. Moreover, future studies should investigate the combination of Aβ1-40(ox)% and CSF alpha-synuclein for the diagnosis of DLB.PMID: 20862375 [PubMed - in process]PMCID: PMC2938459
Related citations 35.
Int J Alzheimers Dis. 2010 Sep 2;2010. pii: 621870.
Alzheimer's proteins, oxidative stress, and mitochondrial dysfunction interplay in a neuronal model of Alzheimer's disease.
Istituto di Biomembrane e Bioenergetica, CNR, Via Amendola 165/A, 70126 Bari, Italy.
Abstract
In this paper, we discuss the interplay between beta-amyloid (Aβ) peptide, Tau fragments, oxidative stress, and mitochondria in the neuronal model of cerebellar granule neurons (CGNs) in which the molecular events reminiscent of AD are activated. The identification of the death route and the cause/effect relationships between the events leading to death could be helpful to manage the progression of apoptosis in neurodegeneration and to define antiapoptotic treatments acting on precocious steps of the death process. Mitochondrial dysfunction is among the earliest events linked to AD and might play a causative role in disease onset and progression. Recent studies on CGNs have shown that adenine nucleotide translocator (ANT) impairment, due to interaction with toxic N-ter Tau fragment, contributes in a significant manner to bioenergetic failure and mitochondrial dysfunction. These findings open a window for new therapeutic strategies aimed at preserving and/or improving mitochondrial function.PMID: 20862336 [PubMed - in process]PMCID: PMC2939402
Related citations 36.
PLoS Genet. 2010 Sep 16;6(9). pii: e1001101.
SNPs associated with cerebrospinal fluid phospho-tau levels influence rate of decline in Alzheimer's disease.
Cruchaga C, Kauwe JS, Mayo K, Spiegel N, Bertelsen S, Nowotny P, Shah AR, Abraham R, Hollingworth P, Harold D, Owen MM, Williams J, Lovestone S, Peskind ER, Li G, Leverenz JB, Galasko D; Alzheimer's Disease Neuroimaging Initiative, Morris JC, Fagan AM, Holtzman DM, Goate AM.
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. cruchagc@psychiatry.wustl.edu
Abstract
Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau(181)) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau(181) levels in two independent CSF series (P(combined) = 1.17 x 10(-05)). We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series (P(combined) = 1.17 x 10(-05)). Our analyses suggest that genetic variants associated with CSF ptau(181) levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ(42) levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF Aβ(42) levels. Finally, we believe genome-wide association studies of CSF tau/ptau(181) levels should identify novel genetic variants which will likely influence rate of progression of AD.PMID: 20862329 [PubMed - in process]PMCID: PMC2940763
Related citations
37.
PLoS One. 2010 Sep 20;5(9). pii: e12845.
Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease.
Ma T, Hoeffer CA, Capetillo-Zarate E, Yu F, Wong H, Lin MT, Tampellini D, Klann E, Blitzer RD, Gouras GK.
Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA.
Abstract
BACKGROUND: The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase that plays a pivotal role in multiple fundamental biological processes, including synaptic plasticity. We explored the relationship between the mTOR pathway and β-amyloid (Aβ)-induced synaptic dysfunction, which is considered to be critical in the pathogenesis of Alzheimer's disease (AD).METHODOLOGY/PRINCIPAL FINDINGS: We provide evidence that inhibition of mTOR signaling correlates with impairment in synaptic plasticity in hippocampal slices from an AD mouse model and in wild-type slices exposed to exogenous Aβ1-42. Importantly, by up-regulating mTOR signaling, glycogen synthase kinase 3 (GSK3) inhibitors rescued LTP in the AD mouse model, and genetic deletion of FK506-binding protein 12 (FKBP12) prevented Aβ-induced impairment in long-term potentiation (LTP). In addition, confocal microscopy demonstrated co-localization of intraneuronal Aβ42 with mTOR.
CONCLUSIONS/SIGNIFICANCE: These data support the notion that the mTOR pathway modulates Aβ-related synaptic dysfunction in AD.
PMID: 20862226 [PubMed - in process]PMCID: PMC2942840
Related citations
38.
J Neurosci. 2010 Sep 22;30(38):12676-89.
Fibrillar amyloid-beta-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer's disease.
Department of Neurological Science, Rush University Medical Center, Chicago, Illinois 60612, USA.
Abstract
Glial activation plays an important role in the pathogenesis of various neurodegenerative disorders including Alzheimer's disease. However, molecular mechanisms by which activated glia could kill neurons are poorly understood. The present study underlines the importance of neutral sphingomyelinase (N-SMase) in mediating the damaging effect of fibrillar amyloid-β 1-42 (Aβ1-42) peptide-activated astroglia on neurons. In transwell experiments, soluble products released from activated primary human astroglia induced the activation of neutral sphingomyelinase (N-SMase), production of ceramide, and cell death in primary human neurons. Protection of neurons from cytotoxic effects of activated astroglia by antisense knockdown of N-SMase, but not acidic sphingomyelinase (A-SMase), suggests that soluble products released from activated astroglia kill neurons via N-SMase but not A-SMase. Next we examined the role of N-SMase in the activation of human astroglia. Interestingly, knockdown of N-SMase, but not A-SMase, by either antisense oligonucleotides or chemical inhibitor, prevented the induction of proinflammatory molecules [tumor necrosis factor-α, inducible nitric oxide synthase, interleukin-1β (IL-1β), and IL-6] and the activation of nuclear factor-κB in Aβ1-42-activated astroglia. Subsequently, fibrillar Aβ peptides also induced the activation of N-SMase and ceramide in vivo in mouse cortex. Most importantly, antisense knockdown of N-SMase, but not A-SMase, decreased the activation of astroglia and protected neurons from fibrillar Aβ toxicity in vivo in the cortex. Together, it is apparent that both the activation of astroglia by Aβ and that the cytotoxicity of activated astroglia on neurons depend on N-SMase.PMID: 20861373 [PubMed - in process]Free Article
Related citations
39.
Psychogeriatrics. 2010 Sep;10(3):117-23. doi: 10.1111/j.1479-8301.2010.00330.x.
The production ratios of AICDε51 and Aβ42 by intramembrane proteolysis of βAPP do not always change in parallel.
Mori K, Okochi M, Tagami S, Nakayama T, Yanagida K, Kodama TS, Tatsumi S, Fujii K, Tanimukai H, Hashimoto R, Morihara T, Tanaka T, Kudo T, Funamoto S, Ihara Y, Takeda M.
Department of Integrated Medicine, Division of Internal Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Abstract
BACKGROUND: During intramembrane proteolysis of β-amyloid protein precursor (βAPP) by presenilin (PS)/γ-secretase, ε-cleavages at the membrane-cytoplasmic border precede γ-cleavages at the middle of the transmembrane domain. Generation ratios of Aβ42, a critical molecule for Alzheimer's disease (AD) pathogenesis, and the major Aβ40 species might be associated with ε48 and ε49 cleavages, respectively. Medicines to downregulate Aβ42 production have been investigated by many pharmaceutical companies. Therefore, the ε-cleavages, rather than the γ-cleavage, might be more effective upstream targets for decreasing the relative generation of Aβ42. Thus, one might evaluate compounds by analyzing the generation ratio of the βAPP intracellular domain (AICD) species (ε-cleavage-derived), instead of that of Aβ42.METHODS: Cell-free γ-secretase assays were carried out to observe de novo AICD production. Immunoprecipitation/MALDI-TOF MS analysis was carried out to detect the N-termini of AICD species. Aβ and AICD species were measured by ELISA and immunoblotting techniques.
RESULTS: Effects on the ε-cleavage by AD-associated pathological mutations around the ε-cleavage sites (i.e., βAPP V642I, L648P and K649N) were analyzed. The V642I and L648P mutations caused an increase in the relative ratio of ε48 cleavage, as expected from previous reports. Cells expressing the K649N mutant, however, underwent a major ε-cleavage at the ε51 site. These results suggest that ε51, as well as ε48 cleavage, is associated with Aβ42 production. Only AICDε51, though, and not Aβ42 production, dramatically changed with modifications to the cell-free assay conditions. Interestingly, the increase in the relative ratio of the ε51 cleavage by the K649N mutation was not cancelled by these changes.
CONCLUSION: Our current data show that the generation ratio of AICDε51 and Aβ42 do not always change in parallel. Thus, to identify compounds that decrease the relative ratio of Aβ42 generation, measurement of the relative level of Aβ42-related AICD species (i.e., AICDε48 and AICDε51) might not be useful. Further studies to reveal how the ε-cleavage precision is decided are necessary before it will be possible to develop drugs targeting ε-cleavage as a means for decreasing Aβ42 production.
PMID: 20860566 [PubMed - in process]Free Article
Related citations40.
ChemMedChem. 2010 Sep 21. [Epub ahead of print]
Novel Huprine Derivatives with Inhibitory Activity toward β-Amyloid Aggregation and Formation as Disease-Modifying Anti-Alzheimer Drug Candidates.
Viayna E, Gómez T, Galdeano C, Ramírez L, Ratia M, Badia A, Clos MV, Verdaguer E, Junyent F, Camins A, Pallàs M, Bartolini M, Mancini F, Andrisano V, Arce MP, Rodríguez-Franco MI, Bidon-Chanal A, Luque FJ, Camps P, Muñoz-Torrero D.
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona (Spain), Fax: (+34) 934035941.
Abstract
A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation and β-secretase (BACE-1), and to cross the blood-brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil-related 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane moiety as the active site and peripheral site to mid-gorge-interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE-induced and self-induced Aβ aggregation, and BACE-1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti-Alzheimer drug candidates with the potential to modify the natural course of this disease.PMID: 20859987 [PubMed - as supplied by publisher]
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