Beta Amyloid Peptide: October 2010

amyloid beta derived diffusible ligand

Neurobiol Dis. 2010 Oct 1. [Epub ahead of print]

17A, a novel non-coding RNA, regulates GABA B alternative splicing and signaling in response to inflammatory stimuli and in Alzheimer disease.

Oncology Biology and Genetics Department (DOBiG), University of Genoa, Genoa, Italy; National Institute for Cancer Research (IST) Genoa, Largo R. Benzi, 10, 16132 Genoa, Italy.

Abstract

Alternative splicing is a central component of human brain complexity; nonetheless, its regulatory mechanisms are still largely unclear. In this work, we describe a novel non-coding (nc) RNA (named 17A) RNA polymerase (pol) III-dependent embedded in the human G-protein-coupled receptor 51 gene (GPR51, GABA B2 receptor). The stable expression of 17A in SHSY5Y neuroblastoma cells induces the synthesis of an alternative splicing isoform that abolish GABA B2 intracellular signaling (i.e., inhibition of cAMP accumulation and activation of K(+) channels). Indeed, 17A is expressed in human brain, and we report that it is upregulated in cerebral tissues derived from Alzheimer disease patients. We demonstrate that 17A expression in neuroblastoma cells enhances the secretion of amyloid β peptide (Aβ) and the Aβ x-42/Αβ x-40 peptide ratio and that its synthesis is induced in response to inflammatory stimuli. These data correlate, for the first time, the activity of a novel pol III-dependent ncRNA to alternative splicing events and, possibly, to neurodegeneration induced by abnormal GABA B function. We anticipate that further analysis of pol III-dependent regulation of alternative splicing will disclose novel regulatory pathways associated to brain physiology and/or pathology.
PMID: 20888417 [PubMed - as supplied by publisher]
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42.
Biochem Biophys Res Commun. 2010 Oct 1. [Epub ahead of print]

Potent inhibitors of amyloid β fibrillization, 4,5-dianilinophthalimide and staurosporine aglycone, enhance degradation of preformed aggregates of mutant Notch3.

Department of Vascular Dementia Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology (NCGG), Aichi, Japan.

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in human NOTCH3. We have recently reported that mutant Notch3 shows a greater propensity to form aggregates, and these aggregates resist degradation, leading to accumulation in the endoplasmic reticulum (ER). In this study, we searched for low-molecular compounds that decrease the amount of mutant Notch3 aggregates. Using a cell-based system, we found that degradation of preformed mutant aggregates was enhanced by treatment with either 4,5-dianilinophthalimide (DAPH) or staurosporine aglycone (SA), both of which inhibit amyloid β (Aβ) fibrillization. Regarding other low-molecular compounds interacting with Aβ fibrils, thioflavin T (ThT) also enhanced the clearance of mutant Notch3. These findings suggest that DAPH, SA, and ThT are potent reagents to dissociate the preformed aggregates of mutant Notch3 by disruption of intermolecular contacts of misfolded proteins. Our study may provide the basis for the development of a pharmacological therapy for CADASIL.
PMID: 20888320 [PubMed - as supplied by publisher]
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43.
Protein Sci. 2010 Sep 30. [Epub ahead of print]

N-terminal engineering of amyloid-β-binding affibody molecules yields improved chemical synthesis and higher binding affinity.

Royal Institute of Technology (KTH), School of Biotechnology, Division of Molecular Biotechnology, AlbaNova University Centre, 106 91 Stockholm, Sweden.

Abstract

The aggregation of amyloid-β (Aβ) peptides is believed to be a major factor in the onset and progression of Alzheimer's disease. Molecules binding with high affinity and selectivity to Aβ-peptides are important tools for investigating the aggregation process. An Aβ-binding Affibody molecule, Z(Aβ3), has earlier been selected by phage display and shown to bind Aβ(1-40) with nanomolar affinity and to inhibit Aβ-peptide aggregation. In this study we create truncated functional versions of the Z(Aβ3) Affibody molecule better suited for chemical synthesis production. Engineered Affibody molecules of different length were produced()by solid phase peptide synthesis (SPPS) and allowed to form covalently linked homodimers by S-S-bridges. The N-terminally truncated Affibody molecules Z(Aβ3)(12-58), Z(Aβ3)(15-58) and Z(Aβ3)(18-58) were produced in considerably higher synthetic yield than the corresponding full-length molecule Z(Aβ3)(1-58). Circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR)-based biosensor analysis showed that the shortest Affibody molecule - Z(Aβ3)(18-58) - exhibited complete loss of binding to the Aβ(1-40)-peptide, while the Z(Aβ3)(12-58) and Z(Aβ3)(15-58) Affibody molecules both displayed approximately one order of magnitude higher binding affinity to the Aβ(1-40)-peptide compared to the full-length Affibody molecule. Nuclear magnetic resonance (NMR) spectroscopy showed that the structure of Aβ(1-40) in complex with the truncated Affibody dimers is very similar to the previously published solution structure of the Aβ(1-40)-peptide in complex with the full-length Z(Aβ3) Affibody molecule. This indicates that the N-terminally truncated Affibody molecules Z(Aβ3)(12-58) and Z(Aβ3)(15-58) are highly promising for further engineering and future use as binding agents to monomeric Aβ(1-40).
PMID: 20886513 [PubMed - as supplied by publisher]
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44.
PLoS One. 2010 Sep 23;5(9):e12853.

Selective disruption of the cerebral neocortex in Alzheimer's disease.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America. rahul@nmr.mgh.harvard.edu

Abstract

BACKGROUND: Alzheimer's disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown.
METHODOLOGY/PRINCIPAL FINDINGS: In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aβ levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals.
CONCLUSIONS/SIGNIFICANCE: Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia.
PMID: 20886094 [PubMed - in process]PMCID: PMC2944799Free PMC Article
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45.
PLoS One. 2010 Sep 23;5(9):e12974.

Phospho-eIF2α level is important for determining abilities of BACE1 reduction to rescue cholinergic neurodegeneration and memory defects in 5XFAD mice.

Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, Orangeburg, New York, United States of America.

Abstract

β-Site APP-cleaving enzyme 1 (BACE1) initiates amyloid-β (Aβ) generation and thus represents a prime therapeutic target in treating Alzheimer's disease (AD). Notably, increasing evidence indicates that BACE1 levels become elevated in AD brains as disease progresses; however, it remains unclear how the BACE1 upregulation may affect efficacies of therapeutic interventions including BACE1-inhibiting approaches. Here, we crossed heterozygous BACE1 knockout mice with AD transgenic mice (5XFAD model) and compared the abilities of partial BACE1 reduction to rescue AD-like phenotypes at earlier (6-month-old) and advanced (15-18-month-old) stages of disease, which expressed normal (∼100%) and elevated (∼200%) levels of BACE1, respectively. BACE1(+/-) deletion rescued memory deficits as tested by the spontaneous alternation Y-maze task in 5XFAD mice at the earlier stage and prevented their septohippocampal cholinergic deficits associated with significant neuronal loss. Importantly, BACE1(+/-) deletion was no longer able to rescue memory deficits or cholinergic neurodegeneration in 5XFAD mice at the advanced stage. Moreover, BACE1(+/-) deletion significantly reduced levels of Aβ42 and the β-secretase-cleaved C-terminal fragment (C99) in 6-month-old 5XFAD mouse brains, while these neurotoxic β-cleavage products dramatically elevated with age and were not affected by BACE1(+/-) deletion in 15-18-month-old 5XFAD brains. Interestingly, although BACE1(+/-) deletion lowered BACE1 expression by ∼50% in 5XFAD mice irrespective of age in concordance with the reduction in gene copy number, BACE1 equivalent to wild-type controls remained in BACE1(+/-)·5XFAD mice at the advanced age. In accord, phosphorylation of the translation initiation factor eIF2α, an important mediator of BACE1 elevation, was dramatically increased (∼9-fold) in 15-18-month-old 5XFAD mice and remained highly upregulated (∼6-fold) in age-matched BACE1(+/-)·5XFAD mice. Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2α-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Aβ/C99 levels and rescue memory deficits and cholinergic neurodegeneration.
PMID: 20886088 [PubMed - in process]PMCID: PMC2944882Free PMC Article
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46.
Magn Reson Med Sci. 2010;9(3):95-9.

Amyloid imaging using high-field magnetic resonance.

Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan.

Abstract

The formation of senile plaques followed by deposition of amyloid β peptides (Aβ) are the earliest pathological changes of Alzheimer's disease (AD); thus, detection of the plaques remains the most important early diagnostic indicator of AD. Amyloid imaging is a noninvasive technique for visualizing senile plaques in the brains of patients with Alzheimer's using positron emission tomography (PET) or magnetic resonance (MR) imaging. Several types of probes have been developed for PET, but few ligands have been developed specifically for MR imaging detection of amyloid plaques. This review presents recent advances in amyloid imaging using MR imaging and includes our studies.
PMID: 20885081 [PubMed - in process]Free Article
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47.
Neuroscience. 2010 Sep 25. [Epub ahead of print]

Low energy laser light (632.8 nm) suppresses amyloid-β peptide-induced oxidative and inflammatory responses in astrocytes.

Department of Biological Engineering, University of Missouri, Columbia, MO 65211, USA.

Abstract

Oxidative stress and inflammation are important processes in the progression of Alzheimer's disease (AD). Recent studies have implicated the role of amyloid β-peptides (Aβ) in mediating these processes. In astrocytes, oligomeric Aβ induces the assembly of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complexes resulting in its activation to produce anionic superoxide. Aβ also promotes production of pro-inflammatory factors in astrocytes. Since low energy laser has previously been reported to attenuate oxidative stress and inflammation in biological systems, the objective of this study was to examine whether this type of laser light was able to abrogate the oxidative and inflammatory responses induced by Aβ. Primary rat astrocytes were exposed to Helium-Neon laser (λ=632.8 nm), followed by the treatment with oligomeric Aβ. Primary rat astrocytes were used to measure Aβ-induced production of superoxide anions using fluorescence microscopy of dihydroethidium (DHE), assembly of NADPH oxidase subunits by the colocalization between the cytosolic p47(phox) subunit and the membrane gp91(phox) subunit using fluorescent confocal microscopy, phosphorylation of cytosolic phospholipase A(2) cPLA(2) and expressions of pro-inflammatory factors including interleukin-1β (IL-1β) and inducible nitric-oxide synthase (iNOS) using Western blot Analysis. Our data showed that laser light at 632.8 nm suppressed Aβ-induced superoxide production, colocalization between NADPH oxidase gp91(phox) and p47(phox) subunits, phosphorylation of cPLA(2,) and the expressions of IL-1β and iNOS in primary astrocytes. We demonstrated for the first time that 632.8 nm laser was capable of suppressing cellular pathways of oxidative stress and inflammatory responses critical in the pathogenesis in AD. This study should prove to provide the groundwork for further investigations for the potential use of laser therapy as a treatment for AD.
PMID: 20884337 [PubMed - as supplied by publisher]
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48.
Eur J Pharmacol. 2010 Sep 29. [Epub ahead of print]

Involvement of notch signaling pathway in amyloid precursor protein induced glial differentiation.

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA.

Abstract

The amyloid precursor protein (APP) has been mainly studied in its role in the production of amyloid β peptides (Aβ), because Aβ deposition is a hallmark of Alzheimer's disease. Although several studies suggest APP has physiological functions, it is still controversial. We previously reported that APP increased glial differentiation of neural progenitor cells (NPCs). In the current study, NPCs transplanted into APP23 transgenic mice primarily differentiated into glial cells. In vitro treatment with secreted APP (sAPP) dose-dependently increased glial fibrillary acidic protein (GFAP) immuno-positive cells in NPCs and over expression of APP caused most NPCs to differentiate into GFAP immuno-positive cells. Treatment with sAPP also dose-dependently increased expression levels of GFAP in NT-2/D1 cells along with the generation of Notch intracellular domain (NICD) and expression of Hairy and enhancer of split 1 (Hes1). Treatment with γ-secretase inhibitor suppressed the generation of NICD and reduced Hes1 and GFAP expressions. Treatment with the N-terminal domain of APP (APP 1-205) was enough to induce up regulation of GFAP and Hes1 expressions, and application of 22 C11 antibodies recognizing N-terminal APP suppressed these changes by sAPP. These results indicate APP induces glial differentiation of NPCs through Notch signaling.
PMID: 20883690 [PubMed - as supplied by publisher]
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49.
Protein Sci. 2010 Sep 29. [Epub ahead of print]

Structurally distinct toxicity inhibitors bind at common loci on β-amyloid fibril.

Department of Chemical & Biochemical Engineering, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore MD 21250.

Abstract

The accumulation of aggregated β-Amyloid (Aβ) in the brain is a hallmark of Alzheimer's Disease (AD) and is thought to play a role in the neurotoxicity associated with the disease. The mechanism by which Aβ aggregates induce toxicity is uncertain. Nonetheless, several small molecules have been found to interact with Aβ fibrils and to prevent their toxicity. In this paper we studied the binding of these known toxicity inhibitors to Aβ fibrils, as a means to explore surfaces or loci on Aβ aggregates that may be significant in the mechanism of action of these inhibitors. We believe knowledge of these binding loci will provide insight into surfaces on the Aβ fibrils important in Aβ biological activity. The program DOCK was used to computationally dock the inhibitors to an Aβ fibril. The inhibitors docked at two shared binding loci, near Lys28 and at the C-termini near Asn27 and Val39. The docking predictions were experimentally verified using lysine specific chemical modifications and Aβ fibrils mutated at Asn27. We found that both Congo red and Myricetin, despite being structurally different, bound at the same two sites. Additionally, our data suggests that three additional Aβ toxicity inhibitors may also bind in one of the sites. Identification of these common binding loci provides targets on the Aβ fibril surface that can be tested in the future for their role in Aβ biological activity.
PMID: 20882638 [PubMed - as supplied by publisher]
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50.
Neurosci Bull. 2010 Oct;26(5):417-27.

Regulation of β cleavage of amyloid precursor protein.

Laboratory of Neural Signal Transduction, Institute of Neuroscience, Shanghai Institutes of Biological Sciences, State Key Laboratory of Neuroscience, Shanghai 200031, China.

Abstract

Alzheimer's disease ranks the first cause for senile dementia. The amyloid cascade is proposed to contribute to the pathogenesis of this disease. In this cascade, amyloid β peptide (Aβ) is produced through a sequential cleavage of amyloid precursor protein (APP) by β and γ secretases, while its cleavage by α secretase precludes Aβ production and generates neurotrophic sAPPα. Thus, enhancing α secretase activity or suppressing β and γ cleavage may reduce Aβ formation and ameliorate the pathological process of the disease. Several regulatory mechanisms of APP cleavage have been established. The present review mainly summarizes the signaling pathways pertinent to the regulation of APP β cleavage.
PMID: 20882069 [PubMed - in process]
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51.
J Neurosci. 2010 Sep 29;30(39):13110-5.

Diabetes-associated SorCS1 regulates Alzheimer's amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex.

Department of Neurology and Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, New York 10029, USA.

Abstract

SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) domain-containing proteins. Both are genetically associated with Alzheimer's disease (AD), and SORL1 expression is decreased in the brains of patients suffering from AD. SORCS1 is also genetically associated with types 1 and 2 diabetes mellitus (T1DM, T2DM). We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer's amyloid-β peptide (Aβ) and the Aβ precursor protein (APP), to test the hypothesis that Sorcs1 deficiency might be a common genetic risk factor underlying the predisposition to AD that is associated with T2DM. Overexpression of SorCS1cβ-myc in cultured cells caused a reduction (p = 0.002) in Aβ generation. Conversely, endogenous murine Aβ(40) and Aβ(42) levels were increased (Aβ(40), p = 0.044; Aβ(42), p = 0.007) in the brains of female Sorcs1 hypomorphic mice, possibly paralleling the sexual dimorphism that is characteristic of the genetic associations of SORCS1 with AD and DM. Since SorL1 directly interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1cβ-myc interacts with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and SorCS1:Vps35 complexes from nontransgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49% (p = 0.009) and total SorL1 protein levels were decreased by 29% (p = 0.003) in the brains of female Sorcs1 hypomorphic mice. From these data, we propose that dysfunction of SorCS1 may contribute to both the APP/Aβ disturbance underlying AD and the insulin/glucose disturbance underlying DM.
PMID: 20881129 [PubMed - in process]
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52.
J Neurosci. 2010 Sep 29;30(39):13089-94.

Transgenic mice with chronic NGF deprivation and Alzheimer's disease-like pathology display hippocampal region-specific impairments in short- and long-term plasticities.

Laboratory of Molecular Mechanisms of Synaptic Plasticity, European Brain Research Institute, 00143 Rome, Italy.

Abstract

The etiology of Alzheimer's disease (AD) remains elusive. The "amyloid" hypothesis states that toxic action of accumulated β-amyloid peptide (Aβ) on synaptic function causes AD cognitive decline. This hypothesis is supported by analysis of familial AD (FAD)-based transgenic mouse models, where altered amyloid precursor protein (APP) processing leads to Aβ accumulation correlating with hippocampal-dependent memory deficits. Some studies report prominent dentate gyrus (DG) glutamatergic plasticity alterations in these mice, while CA1 plasticity remains relatively unaffected. The "neurotrophic unbalance" hypothesis, on the other hand, states that AD-related loss of cholinergic signaling and altered APP processing are due to alterations in nerve growth factor (NGF) trophic support. This hypothesis is supported by analysis of the AD11 mouse, which exhibits chronic NGF deprivation during adulthood and displays AD-like pathology, including Aβ accumulation and hippocampal-dependent memory deficits. In this study, we analyzed CA1 and DG glutamatergic plasticity in AD11 mice to evaluate whether these mice also share with FAD models a common phenotype in hippocampal synaptic dysfunction. We report that AD11 mice display age-dependent short- and long-term DG plasticity deficits, while CA1 plasticity remains relatively spared. We also report that both structures exhibit enhanced glutamatergic transmission under lower, yet physiological, neurotransmitter release conditions, a defect that should be considered when further evaluating hippocampal synaptic deficits underlying AD pathology. We conclude that severe deficits in DG plasticity represent another common denominator between these two etiologically different types of AD mouse models, independent of the initial insult (overexpression of FAD mutation or NGF deprivation).
PMID: 20881126 [PubMed - in process]
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53.
Phytother Res. 2010 Oct;24(10):1538-42.

Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells.

School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

Abstract

Amyloid β peptide (Aβ) induced toxicity is a well-established pathway of neuronal cell death which might play a role in Alzheimer's disease. In this regard, the toxic effect of Aβ on a cultured Aβ-sensitive neuronal cell line was used as a primary screening tool for potential anti-Alzheimer's therapeutic agents. The effects of nine pure compounds (vitamin E, α-asarone, salidroside, baicolin, magnolol, gastrodin, bilobalide, honokiol and β-asarone) from selected Chinese herbs on neuronal cell death induced by Aβ in NGF-differentiated PC12 cells were examined. Only two of the studied compounds, honokiol and magnolol, significantly decreased Aβ-induced cell death. Further experiments indicated that their neuroprotective effects are possibly mediated through reduced ROS production as well as suppression of intracellular calcium elevation and inhibition of caspase-3 activity. The results provide for the first time a scientific rationale for the clinical use of honokiol and magnolol in the treatment of Alzheimer's disease.
PMID: 20878707 [PubMed - in process]
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54.
J Biol Chem. 2010 Sep 28. [Epub ahead of print]

Statins promote the degradation of extracellular amyloid {beta}-peptide by microglia via stimulation of exosome-associated IDE secretion.

University Hospital Bonn, Germany;

Abstract

Epidemiological studies indicate that intake of statins decrease the risk of developing Alzheimer's disease (AD). Cellular and in vivo studies suggested that statins might decrease the generation of the amyloid β-peptide (Aβ) from the β-amyloid precursor protein (APP). Here, we show that statins potently stimulate the degradation of extracellular Aβ by microglia. The statin-dependent clearance of extracellular Aβ is mainly exerted by insulin degrading enzyme (IDE) which is secreted in a non-conventional pathway in association with exosomes. Stimulated IDE secretion and Aβ degradation was also observed in blood of mice upon peripheral treatment with lovastatin. Importantly, increased IDE secretion upon lovastatin treatment was dependent on protein isoprenylation and upregulation of exosome secretion by fusion of multivesicular bodies (MVBs) with the plasma membrane. These data demonstrate a novel pathway for the non-conventional secretion of IDE via exosomes. The modulation of this pathway could provide a new strategy to enhance the extracellular clearance of Aβ.
PMID: 20876579 [PubMed - as supplied by publisher]Free Article
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55.
Neuroscience. 2010 Sep 27. [Epub ahead of print]

Cloning, sequencing and expression in the dog of the main amyloid precursor protein isoforms and some of the enzymes related with their processing.

Montecanal Laboratory, Araclon Biotech, Zaragoza, Spain.

Abstract

Alzheimer's disease (AD) is characterized by neuronal loss and the presence of both neurofibrillary tangles and senile plaques in the brain. These plaques arise from the deposition of beta-amyloid (Aβ) peptides (38-43 amino acids), which are generated from enzymatic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. In the present work, we cloned the principal APP isoforms as well as some enzymes that have been implicated in their amyloidogenic and non-amyloidogenic processing in dogs. Additionally, the main proteases implicated in the degradation of Aβ were also studied. We also investigated the level of expression of these APP isoforms and enzymes in different brain regions and in peripheral tissues. Our data demonstrate that these canine proteins are highly homologous to their human counterparts. In addition, the expression pattern of these proteins in dogs is consistent with previous data reported in human beings. Thus, dogs may be a natural model to study the biology of AD and could also serve as an animal model for Aβ-targeted drugs against this devastating disease.
PMID: 20875843 [PubMed - as supplied by publisher]
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56.
Brain Res. 2010 Sep 25. [Epub ahead of print]

Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer's disease.

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.

Abstract

Synaptic pathology occurs early in Alzheimer's disease (AD) development, and cerebrospinal fluid biomarkers for synaptic damage may be altered early in the disease process. In the present study we examined cerebrospinal fluid levels of the postsynaptic protein neurogranin in patients with mild cognitive impairment (MCI) or AD and controls. The low neurogranin level in cerebrospinal fluid required enrichment by immunoprecipitation prior to mass spectrometric identification and semi-quantitative immunoblot analysis. Relative quantification revealed a significant increase of neurogranin in the AD group compared with controls, while the MCI group was not statistically different from either controls or the AD group. The concentration of the AD biomarkers T-tau, P-tau(181) and Aβ(42) were significantly changed in the control and MCI groups compared with the AD group, but no significant differences were found between the MCI group and controls for the three biomarkers. Nevertheless, a trend towards increasing levels of neurogranin, T-tau and P-tau(181) was found in cerebrospinal fluid from MCI patients compared with controls. The elevated neurogranin levels in the MCI and AD groups might reflect synaptic degeneration. These results together suggest that cerebrospinal fluid neurogranin might be valuable together with the established AD biomarkers in the early diagnosis of AD and warrants further studies to determine the diagnostic value of neurogranin.
PMID: 20875798 [PubMed - as supplied by publisher]
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57.
J Am Chem Soc. 2010 Sep 28. [Epub ahead of print]

Combination of Kinetically Selected Inhibitors in Trans Leads to Highly Effective Inhibition of Amyloid Formation.

Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, and Department of Medicine, New York University Medical Center, 550 First Avenue, New York, New York 10016.

Abstract

Amyloid formation plays a role in over 25 human disorders. A range of strategies have been applied to the problem of developing inhibitors of amyloid formation, but unfortunately, many inhibitors are effective only in molar excess and typically either lengthen the time to the onset of amyloid formation, (the lag time), while having modest effects on the total amount of amyloid fibrils produced, or decrease the amount of amyloid without significantly reducing the lag time. We demonstrate a general strategy whereby two moderate inhibitors of amyloid formation can be rationally selected via kinetic assays and combined in trans to yield a highly effective inhibitor which dramatically delays the time to the appearance of amyloid and drastically reduces the total amount of amyloid formed. A key feature is that the selection of the components of the mixture is based on their effect on the time course of amyloid formation rather than on just the amount of amyloid produced. The approach is validated using inhibitors of amyloid formation by islet amyloid polypeptide, the causative agent of amyloid formation in type 2 diabetes and the Alzheimer's disease Aβ peptide.
PMID: 20873820 [PubMed - as supplied by publisher]
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58.
Zhong Yao Cai. 2010 May;33(5):763-7.

[The protective effect of puerarin on Abeta(25-35)-induced PC12 cell injury]

[Article in Chinese]
Department of Anatomy, Hainan Medical College, Haikou 571101, China. hyzhang_xjtu@yahoo.cn

Abstract

OBJECTIVE: To study The protective effect of puerarin on Abeta(25-35)-induced PC12 cell injury.
METHODS: PC12 cells were treated with puerarin for 0.5 h, then incubated with Abeta(25-35) (50 micromol/L) for 24 h to investigate the production of reactive oxygen species (ROS), mitochondrial membrane potential levels and Caspase-3 activation; The expressions of Bax, bcl-2 were measured by Western Blotting.
RESULTS: Preincubation of the cell with puerarin could inhibit the ROS and increase mitochondrial membrane potential levels. Puerarin was also found to increase the Bcl-2/Bax ratio and reduce Caspase-3 activation.
CONCLUSION: Puerarin may act as an intracellular ROS scavenger, and its antioxidant properties may protect against Abeta(25-35)-induced cell injury.
PMID: 20873562 [PubMed - in process]
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59.
Biopolymers. 2010 Sep 24. [Epub ahead of print]

CD measurements of β-amyloid (1-40) and (1-42) in the condensed phase.

Japan Science and Technology Agency, ERATO-SORST Kuroda Chiromorphology Team, 4-7-6 Komaba, Meguro-ku, Tokyo, 153-0041, Japan.

Abstract

Circular Dichroism (CD) spectroscopy of proteins/peptides in thin films can provide valuable information on the structures in the aggregated states, however, it is difficult to estimate the secondary structure content quantitatively due to artifact signals arising from macroscopic anisotropies which is unique to the solid phase. Using a Universal Chiroptical Spectrophotometer (UCS-1) together with the measurement and analytical procedures we have developed, we could obtain artifact-free CD spectra of cast and Langmuir-Blodgett (L-B) films of synthetic peptides, Aβ (1-40) and (1-42) which are related to Alzheimer's disease. The work gave insights into the mechanisms for structural transformation and amyloid-like aggregation. © 2010 Wiley Periodicals, Inc. Biopolymers, 2010.
PMID: 20872872 [PubMed - as supplied by publisher]
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60.
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
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Parkinson's Disease Gene Captain, PGC-1α, Abandons Mitochondria in PD

8 October 2010. If you want to alter a ship’s course, you don’t go to the deck swabs or the cabin boys. You go straight to the captain. In Parkinson disease, that “captain” may be a master transcription regulator on which mitochondrial function depends, according to a paper in the October 6 Science Translational Medicine. A multinational consortium of researchers report that peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α to its friends) manages multiple genes that mitochondria need for biogenesis, electron transport, and glucose metabolism (Lin et al., 2005). The authors suggest that activating PGC-1α could slow the course of Parkinson’s.
“It is all pointing to the mitochondria,” said senior author Clemens Scherzer, who works at Harvard Medical School along with first author Bin Zheng. The project, a meta-analysis encompassing 17 studies and samples from 410 people, is the first publication to result from the Global PD Gene Expression (GPEX) Consortium. Researchers banded together in 2003 to search for cellular processes that are affected in PD. Then, according Scherzer, they had to wait for enough studies to be conducted. Further, the researchers had to devise the proper statistical tools. “Nobody had done this gene set meta-analysis before,” Scherzer said. The approach is “appealing,” commented Vamsi Mootha of Harvard Medical School, who was not involved in the study, by e-mail.
The current analysis is different from a genomewide association study (GWAS), in which scientists search for individual genetic factors that influence disease. In this genomewide expression study (GWES), Scherzer and colleagues were looking for subtle changes in the mRNA profiles of people with PD. They reasoned that a single gene change might be too small to appear significant in their analysis. Instead, they looked for associations between PD and sets of genes with similar function. Thus, they compared PD status to mRNA profiles of 522 overlapping gene families. This kind of analysis makes several small changes in expression of related genes detectable.
Expression of mutant α-synuclein in cultured neurons (microtubule-associated protein 2, red) normally causes dopaminergic neurons (tyrosine hydroxylase, green) to retract their processes and die. But with additional PGC-1α expression, the neurons survive. Image credit: Science/AAAS/Jean-Christophe Rochet, Purdue University, West Lafayette, Indiana
The study included three stages. In the first stage of their project, the GPEX scientists collected gene expression data from nine studies of human substantia nigra tissue, collected at autopsy. Some samples were whole substantia nigras and some were laser-captured dopaminergic neurons (see related ARF Webinar). By comparing 99 PD cases and 86 age- and gender-matched controls, the researchers found that 28 of the 522 gene sets were broadly under-expressed in people with Parkinson’s. Many of these gene sets encoded cellular bioenergetics pathways.
This stage one experiment told the scientists about the final phase of Parkinson disease, at time of death. But Scherzer is interested in the changes that happen early on, even before symptoms start, in order to find treatments that might slow or halt neurodegeneration. Therefore, the consortium scientists collected tissue from 16 cases of subclinical PD for their stage two analysis. These samples came from people who had no recorded symptoms of Parkinson disease, but who, upon autopsy, evinced Lewy body pathology. As such, they likely were on the road to Parkinson’s, Scherzer said. The researchers analyzed their 28 gene sets in these cases versus 17 controls, and concluded that 12 gene sets were affected in early PD.
The first two stages were based on substantia nigra tissue, but it is increasingly recognized that PD pathology affects other parts of the brain, as well as blood cells (Alafuzoff et al., 2008; Haas et al., 1995). So for stage three, in a further seven data sets, Scherzer and colleagues examined other tissues: the frontal and prefrontal cortices, basal ganglia structures, and blood. Based on 106 diagnosed PD cases and 86 controls, the researchers narrowed their 12 gene sets down to 10 that are under-expressed in PD.
The 10 gene sets were all related to electron transport and glucose utilization. The set most tightly associated with PD was a 95-gene family of nuclear-encoded electron transport chain genes. Another strongly linked set was a family that functions in pyruvate uptake. Krebs cycle participants were also affected.
This widespread deterioration of mitochondrial pathways, Scherzer said, suggests a “pervasive” defect in the organelle’s function, affecting all neurons as well as blood cells. He speculated that dopaminergic neurons, with their hunger for energy and their production of stressful free radicals, might be particularly susceptible to mitochondrial dysfunction.
Scherzer’s acute interest was drawn by a set of 425 genes united by their dependence on the master transcription regulator PGC-1α. These genes encode proteins for electron transport as well as translation, folding, and import of mitochondrial proteins. It is not yet known if expression of PGC-1α itself is altered in PD tissues, or if the action of the protein is otherwise compromised.
To further examine the role of PGC-1α, Scherzer and colleagues teamed up with Jean-Christophe Rochet, of Purdue University in West Lafayette, Indiana, for cell culture experiments. The researchers worked with two cellular PD models: One system was primary rat neural cultures transfected with α-synuclein carrying a PD-linked mutation. The other was human catecholaminergic SH-SY5Y cells treated with rotenone, a pesticide linked to PD. In both kinds of cultures, overexpression of human PGC-1α activated the electron transport chain, allowed cells to retain neural processes, and kept more cells alive. The results fit with work in mice showing that PGC-1α knockout mice are more susceptible to MPTP treatment, which causes PD-like symptoms, than are wild-type animals (see ARF related news story on St-Pierre et al., 2006). Mootha suggested that crosses between PGC-1α-overexpressing mice and genetic neurodegeneration models would further strengthen the scientists’ conclusions.
“The current study, in combination with a wealth of prior studies, points to the mitochondrion as an attractive target for neurodegenerative disorders,” Mootha added. Lewy bodies frequently contain degenerating mitochondria (Roy and Wolman, 1969). Electron transport dysfunction, as well, occurs in Parkinson disease (reviewed in Henchcliffe and Beal., 2008; Parker et al., 2008; Keeney et al., 2006). Mutations in PINK1, PARK2, and SNCA disrupt mitochondria and cause PD (Park et al., 2006; ARF related news story on Greene et al., 2003; Devi et al., 2008).
All that evidence has scientists eyeing the mitochondrion as a place to send their drugs. “At present,” Mootha wrote, “it is not clear what the best approach might be—perhaps targeting [PGC-1α], perhaps something upstream, or perhaps tuning a specific bioenergetic parameter of the mitochondrion.”
Of those options, PGC-1α is an appealing target because drugs are already available. PGC-1α is involved in metabolic syndromes, including diabetes, and the FDA has approved some activators. Scherzer is currently testing these compounds in cultured neurons to find those that best activate PGC-1α.
The research could have implications beyond Parkinson disease. PGC-1α loss also causes Huntington disease-like symptoms in mice (see ARF related news story on Lin et al., 2004), and scientists have long considered its receptor, PPARγ, as a potential target in Alzheimer disease (see ARF Live Discussion). Diabetes drugs targeting PPARγ, however, have not so far succeeded in clinical trials (see ARF related news story).
Scherzer hopes turning up PGC-1α and its associated host of mitochondrial-boosting genes could slow Parkinson’s. However, he noted, by the time people show symptoms, they have generally lost 70 percent of their dopaminergic neurons in the affected brain areas. People tend to have PD pathology in the brain five or more years before they have trouble moving (Savica et al., 2010). So the success of a PGC-1α therapy would depend on the current hunt for biomarkers that identify Parkinson’s early (see Scherzer, 2009).
The PGEX Consortium has other projects in the works, Scherzer said, “This is hopefully our first installment of many.” The group is working on a similar GWES meta-analysis in animal models of PD. In addition, they are developing a publicly accessible database similar to PDGene. Scherzer hopes the project will allow anyone to log on and “get sort of a hit parade of transcripts and genes in Parkinson disease.”—Amber Dance.
Reference:
Zheng B, Liao Z, Locascio JJ, Lesniak KA, Roderick SS, Watt ML, Eklund AC, Zhang-James Y, Kim PD, Hauser MA, Grünblatt E, Moran LB, Mandel SA, Riederer P, Miller RM, Federoff HJ, Wüllner U, Papapetropouos S, Youdim MB, Cantuti-Castelvetri I, Young AB, Vance JM, Davis RL, Hedreen JC, Adler CH, Beach TG, Graeber MB, Middleton FA, Rochet JC, Scherzer CR, the Global PD Gene Expression (GPEX) Consortium. PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med. 2010 Oct 6;2(52):52ra73.

Amyloid Beta Peptides

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
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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.

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]
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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]
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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]
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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.

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]
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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]
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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.

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
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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
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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
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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.

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
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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.

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
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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
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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.

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
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40.
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.

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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