Accumulation Of Amyloid Beta Protein Research Articles

Sirtuins as Novel Targets for Alzheimer's Disease and Other Neurodegenerative Disorders: Experimental and Genetic Evidence

Sirtuins are a family of conserved proteins with deacetylase and ADP-ribosyltransferase activity. In humans they are coded by seven genes (SIRT1-7). The most widely investigated and best known sirtuin is SIRT1, which can be activated by the natural phytocompound resveratrol and plays a role in several physiologic (embryogenesis, glucose metabolism, apoptosis, autophagy, chromatin integrity, and transcriptional state) and pathologic (diabetes, cancer, cardiovascular disorders, and neurodegeneration) conditions. In the field of neurodegeneration, resveratrol and SIRT1 have proved beneficial in in vitro and in vivo models of Alzheimer's disease (AD), reducing amyloid-beta protein accumulation, considered one of the pathogenic mechanisms. In contrast to these promising biological data, however, genetic studies linking SIRT1 variability to AD are negative (this is the case for other sirtuins too, e.g., SIRT3). In this review, we summarize the in vitro, in vivo, and genetic experimental results linking SIRT1 and the other sirtuins to AD, while a description of sirtuins' biochemical features and modulating compounds, as well as sirtuins' involvement in other neurodegenerative disorders are discussed as collateral aims.

Biomarkers in Alzheimer’s Disease—Perspectives for the Future

Alzheimer’s disease (AD) is characterized pathologically by the overproduction or excessive accumulation of amyloid beta protein leading to the deposition of diffuse and neuriric plaques. Hyperphosphorylation of tau protein promotes the accumulation of intracellular neurofibrillary tangles. These events comprise a pathological cascade in the AD brain that includes oxidation, inflammation, excitotoxicity, and apoptosis with activation of myriad associated intracellular pathways. Some of these neuropathological changes are detectable by biomarkers such as neuroimaging or serum or cerebrospinal fluid (CSF) measures. Magnetic resonance imaging (MRI) reveals cerebral atrophy, fluorodeoxyglucose positron emission tomography (FDG-PET) shows regional brain hypometabolism, amyloid imaging demonstrates fibrillar amyloid in plaques, and CSF measures reveal decreased levels of the amyloid protein and increased levels of total tau protein and hyperphosphorylated tau. These biomarkers provide the basis for identifying and characterizing asymptomatic pre-clinical AD pathology, minimally symptomatic prodromal AD, and AD type dementia. Biomarkers have an increasingly important role in AD care and research at all stages of disease, and promise to assist in the development of new AD therapies.

Two Disaccharides and Trimethylamine N-Oxide Affect Aβ Aggregation Differently, but All Attenuate Oligomer-Induced Membrane Permeability

Interaction between aggregates of amyloid beta protein (Abeta) and membranes has been hypothesized by many to be a key event in the mechanism of neurotoxicity associated with Alzheimer's disease (AD). Proposed membrane-related mechanisms of neurotoxicity include ion channel formation, membrane disruption, changes in membrane capacitance, and lipid membrane oxidation. Recently, osmolytes such as trehalose have been found to delay Abeta aggregation in vitro and reduce neurotoxicity. However, no direct measurements have separated the effects of osmolytes on Abeta aggregation versus membrane interactions. In this article, we tested the influence of trehalose, sucrose and trimethylamine-N-oxide (TMAO) on Abeta aggregation and fluorescent dye leakage induced by Abeta aggregates from liposomes. In the absence of lipid vesicles, trehalose and sucrose, but not TMAO, were found to delay Abeta aggregation. In contrast, all of the osmolytes significantly attenuated dye leakage. Dissolution of preformed Abeta aggregates was excluded as a possible mechanism of dye leakage attenuation by measurements of Congo red binding as well as hydrogen-deuterium exchange detected by mass spectrometry (HX-MS). However, the accelerated conversion of high order oligomers to fibril caused by vesicles did not take place if any of the three osmolytes presented. Instead, in the case of disaccharide, osmolytes were found to form adducts with Abeta, and change the dissociation dynamics of soluble oligomeric species. Both effects may have contributed to the observed osmolyte attenuation of dye leakage. These results suggest that disaccharides and TMAO may have very different effects on Abeta aggregation because of the different tendencies of the osmolytes to interact with the peptide backbone. However, the effects on Abeta membrane interaction may be due to much more general phenomena associated with osmolyte enhancement of Abeta oligomer stability and/or direct interaction of osmolyte with the membrane surface.

Docosahexaenoic acid supplementation of primary rat hippocampal neurons attenuates the neurotoxicity induced by aggregated amyloid beta protein 42 and up-regulates cytoskeletal protein expression

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by extracellular deposits of fibrillar aggregates of amyloid-β peptide (Aβ). Levels of docosahexaenoic acid (DHA, 22:6n-3), the major fatty acid component of the neuronal membrane, are reduced in the AD hippocampus. We hypothesized that hippocampal neurons with reduced DHA levels would be more susceptible to aggregated Aβ-induced death and that this might be overcome by increasing hippocampal neuronal DHA levels. Embryonic Day 18 rat hippocampal cells were cultured in neurobasal medium with B27 supplemented with 0–100 μM DHA for 8 days, then were treated with 5 μM aggregated Aβ 42 for 1 day. We found that supplementation with 5–10 μM DHA, which resulted in hippocampal neuron DHA levels of 12–16% of total fatty acids, was optimal for primary hippocampal neuronal survival, whereas supplementation with 5 or 25 μM DHA attenuated aggregated Aβ 42-induced neurotoxicity and protected hippocampal neurons, with 25 μM DHA being more effective. DHA supplementation also resulted in significant up-regulation of expression of tyrosine tubulin and acetylated tubulin. We suggest that hippocampal neuronal DHA levels may be critical for AD prevention by attenuating the neurotoxicity induced by Aβ and in maintaining hippocampal neuron survival.

Quantitative and Mechanistic Studies of Aβ Immunotherapy

There is substantial and compelling evidence that aggregation and accumulation of amyloid beta protein (Abeta) plays a pivotal role in the development of Alzheimer's disease (AD); thus, numerous strategies to prevent Abeta aggregation and accumulation or to facilitate removal of preexisting deposits of Abeta are being evaluated as ways to treat or prevent AD. Pre-clinical studies in mice demonstrate the therapeutic potential of altering Abeta deposition by inducing a humoral immune response to fibrillar Abeta42 (fAbeta42) or passively administering anti-Abeta antibodies (Abs), and both passive and active anti-Abeta immunotherapeutic approaches are now being tested in humans. Although a variety of mechanisms have been postulated regarding how Abeta immunotherapy might work to attenuate or in some circumstances clear Abeta from the brain, no mechanism has been definitively proven or disproven. Herein, we will review the various mechanisms that have been postulated. In addition we will discuss how a more thorough understanding of the pharmacokinetics of anti-Abeta Abs and their effects on Abeta levels and turnover provides insight into both the therapeutic potential and limitation of Abeta immunotherapy. We will conclude with a discussion of additional experimentation required to better understand the mechanism of action of anti-Abeta Abs in AD and optimize antibody (Ab) mediated therapy for AD.

Are Biomarkers Valid as Surrogates for Treatment Effects in Alzheimer’s Disease?

Diagnosis of Alzheimer’s disease (AD), the most common form of dementia, involves neuropsychological testing, limited laboratory tests and brain imaging. Current therapeutic options for AD are symptomatic treatments that target dysfunctional neurotransmitters associated with the disorder. Recent research has focused on therapeutic strategies that inhibit the production and aggregation of amyloid beta protein (Aβ) in plaques and increase its clearance from the brain. Such strategies are likely to be most effective at pre-clinical stages of the disease, before widespread synaptic and neuronal loss occurs. Thus, there is a need for biomarkers that predict disease course and outcome and monitor disease progression and treatment efficacy. The development of such biomarkers for AD is critical to translating the efficacy of new therapies.

Promoter polymorphisms which modulate insulin degrading enzyme expression may increase susceptibility to Alzheimer's disease

Cerebral accumulation of amyloid beta protein (Aβ) is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Insulin degrading enzyme (IDE) is involved in Aβ degradation, therefore the gene encoding for insulin degrading enzyme is one of the candidate genes risky for AD. In Chinese Han populations we found three polymorphisms in IDE promoter: −1002T/G (rs3758505), −179T/C (rs4646953) and −51C/T (rs4646954). The −1002T and −51C alleles were over-represented in 357 sporadic AD (SAD) patients when compared to those in 331 healthy individuals. Furthermore, −1002T/G and −51C/T were in strong linkage disequilibrium and they constructed a relatively risky −1002T/−51C and a relatively protective −1002G/−51T. Luciferase reporter assay indicated −1002T/−51C had lower transcriptional activity than −1002G/−51T. A more marked increase in −1002T/−51C transcriptional activity was seen when under Aβ 25–35 and serum deprivation treatment. The present study provides evidence that IDE promoter polymorphisms that significantly decrease IDE expression levels are associated with development of SAD.

Effects of ginkgo biloba extract EGb761 on expression of RAGE and LRP-1 in cerebral microvascular endothelial cells under chronic hypoxia and hypoglycemia

Alzheimer's disease (AD), characterized by accumulation of amyloid-beta protein (Abeta) in brain parenchyma, is closely associated with brain ischemia. Decreased clearance of Abeta from brain is the main cause of Abeta accumulation in sporadic AD. However, the mechanisms underlying ischemia-mediated AD pathogenesis remain unclear. The receptor for advanced end glycation products (RAGE) and low-density lipoprotein receptor-related protein-1 (LRP-1) expressed at blood brain barrier (BBB) are actively involved in Abeta clearance. RAGE is thought to be a primary transporter of Abeta across BBB into the brain from the systemic circulation, while LRP-1 mediates the transport of Abeta out of the brain. Ginkgo biloba extract EGb761, a traditional Chinese medicine, has been widely used in the treatment of AD. To investigate the effects of EGb761 on the expression of RAGE and LRP-1 in endothelial cells in response to ischemic injury, we cultured bEnd.3 cells, an immortalized mouse cerebral microvessel endothelial cell line, under a chronic hypoxic and hypoglycemic condition (CHH) to mimic ischemic injury of BBB, and then treated with EGb 761. We found that EGb 761 markedly ameliorated the damage (evaluated by MTT assay) from CHH. Moreover, we demonstrated that CHH led to a significant increase in the expression of RAGE both at the mRNA and protein levels at all times (24, 36, and 48 h), conversely; CHH induced a dramatic decrease in LRP-1 mRNA and protein expression at both 36 and 48 h. The results indicated that CHH has differential effects on the expression of RAGE and LRP-1. Furthermore, EGb761 significantly reversed CHH-induced upregulation of RAGE expression and downregulation of LRP-1 expression. Our findings suggest that EGb761 favor clearance of Abeta via regulating the expression of RAGE and LRP-1 during brain ischemia. This may provide a new insight into a possible molecular mechanism underlying brain ischemia-mediated AD pathogenesis, and potential therapeutic application of EGb 761 in treatment of AD.

Mechanisms of Hybrid Oligomer Formation in the Pathogenesis of Combined Alzheimer's and Parkinson's Diseases

BackgroundMisfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer's disease (AD) and Parkinson's disease (PD) are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid β protein (Aβ) oligomers has been identified as one of the central toxic events in AD, accumulation of α-synuclein (α-syn) resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD). We have recently shown that Aβ promotes α-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear.Methodology/Principal FindingsIn order to understand the molecular mechanisms involved in potential Aβ/α-syn interactions, immunoblot, molecular modeling, and in vitro studies with α-syn and Aβ were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Aβ and α-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Aβ binds α-syn monomers, homodimers, and trimers, forming hybrid ring-like pentamers. Interactions occurred between the N-terminus of Aβ and the N-terminus and C-terminus of α-syn. Interacting α-syn and Aβ dimers that dock on the membrane incorporated additional α-syn molecules, leading to the formation of more stable pentamers and hexamers that adopt a ring-like structure. Consistent with the simulations, under in vitro cell-free conditions, Aβ interacted with α-syn, forming hybrid pore-like oligomers. Moreover, cells expressing α-syn and treated with Aβ displayed increased current amplitudes and calcium influx consistent with the formation of cation channels.Conclusion/SignificanceThese results support the contention that Aβ directly interacts with α-syn and stabilized the formation of hybrid nanopores that alter neuronal activity and might contribute to the mechanisms of neurodegeneration in AD and PD. The broader implications of such hybrid interactions might be important to the pathogenesis of other disorders of protein misfolding.

Tg-SwDI Transgenic Mice Exhibit Novel Alterations in AβPP Processing, Aβ Degradation, and Resilient Amyloid Angiopathy

Alzheimer's disease (AD) is characterized by the accumulation of extracellular insoluble amyloid, primarily derived from polymerized amyloid-beta (Abeta) peptides. We characterized the chemical composition of the Abeta peptides deposited in the brain parenchyma and cerebrovascular walls of triple transgenic Tg-SwDI mice that produce a rapid and profuse Abeta accumulation. The processing of the N- and C-terminal regions of mutant AbetaPP differs substantially from humans because the brain parenchyma accumulates numerous, diffuse, nonfibrillar plaques, whereas the thalamic microvessels harbor overwhelming amounts of compact, fibrillar, thioflavine-S- and apolipoprotein E-positive amyloid deposits. The abundant accretion of vascular amyloid, despite low AbetaPP transgene expression levels, suggests that inefficient Abeta proteolysis because of conformational changes and dimerization may be key pathogenic factors in this animal model. The disruption of amyloid plaque cores by immunotherapy is accompanied by increased perivascular deposition in both humans and transgenic mice. This analogous susceptibility and response to the disruption of amyloid deposits suggests that Tg-SwDI mice provide an excellent model in which to study the functional aftermath of immunotherapeutic interventions. These mice might also reveal new avenues to promote amyloidogenic AbetaPP processing and fundamental insights into the faulty degradation and clearance of Abeta in AD, pivotal issues in understanding AD pathophysiology and the assessment of new therapeutic agents.

Cerebral Amyloid-Beta Protein Accumulation with Aging in Cotton-Top Tamarins: A Model of Early Alzheimer's Disease?

Alzheimer's disease (AD) is the most common progressive form of dementia in the elderly. Two major neuropathological hallmarks of AD include cerebral deposition of amyloid-beta protein (Abeta) into plaques and blood vessels, and the presence of neurofibrillary tangles in brain. In addition, activated microglia and reactive astrocytes are often associated with plaques and tangles. Numerous other proteins are associated with plaques in human AD brain, including Apo E and ubiquitin. The amyloid precursor protein and its shorter fragment, Abeta, are homologous between humans and non-human primates. Cerebral Abeta deposition has been reported previously for rhesus monkeys, vervets, squirrel monkeys, marmosets, lemurs, cynomologous monkeys, chimpanzees, and orangutans. Here we report, for the first time, age-related neuropathological changes in cotton-top tamarins (CTT, Saguinus oedipus), an endangered non-human primate native to the rainforests of Colombia and Costa Rica. Typical lifespan is 13-14 years of age in the wild and 15-20+ years in captivity. We performed detailed immunohistochemical analyses of Abeta deposition and associated pathogenesis in archived brain sections from 36 tamarins ranging in age from 6-21 years. Abeta plaque deposition was observed in 16 of the 20 oldest tamarins (>12 years). Plaques contained mainly Abeta42, and in the oldest animals, were associated with reactive astrocytes, activated microglia, Apo E, and ubiquitin-positive dystrophic neurites, similar to human plaques. Vascular Abeta was detected in 14 of the 20 aged tamarins; Abeta42 preceded Abeta40 deposition. Phospho-tau labeled dystrophic neurites and tangles, typically present in human AD, were absent in the tamarins. In conclusion, tamarins may represent a model of early AD pathology.

Simultaneous monitoring of peptide aggregate distributions, structure, and kinetics using amide hydrogen exchange: Application to Aβ(1‐40) fibrillogenesis

Increasing evidence indicates that soluble aggregates of amyloid beta protein (Abeta) are neurotoxic. However, difficulty in isolating these unstable, dynamic species impedes studies of Abeta and other aggregating peptides and proteins. In this study, hydrogen-deuterium exchange (HX) detected by mass spectrometry (MS) was used to measure Abeta(1-40) aggregate distributions without purification or modification that might alter the aggregate structure or distribution. Different peaks in the mass spectra were assigned to monomer, low molecular weight oligomer, intermediate, and fibril based on HX labeling behavior and complementary assays. After 1 h labeling, the intermediates incorporated approximately ten more deuterons relative to fibrils, indicating a more solvent exposed structure of such intermediates. HX-MS also showed that the intermediate species dissociated much more slowly to monomer than did the very low molecular weight oligomers that were formed at very early times in Abeta aggregation. Atomic force microscopy (AFM) measurements revealed the intermediates were roughly spherical with relatively homogenous diameters of 30-50 nm. Quantitative analysis of the HX mass spectra showed that the amount of intermediate species was correlated with Abeta toxicity patterns reported in a previous study under the same conditions. This study also demonstrates the potential of the HX-MS approach to characterizing complex, multi-component oligomer distributions of aggregating peptides and proteins.

Network dysfunction in Alzheimer's disease: does synaptic scaling drive disease progression?

Accumulation of beta-amyloid protein (Abeta) in the brain is a key feature of Alzheimer's disease (AD). The build-up of aggregated forms of Abeta leads to synaptic loss and to cognitive dysfunction. Although the pathways controlling production and aggregation of Abeta are well studied, the mechanisms that drive the spread of neurodegeneration in the brain are unclear. Here, the idea is presented that AD progresses as a consequence of synaptic scaling, a type of neuronal plasticity that helps maintain synaptic signal strength. Recent studies indicate that brain-derived neurotrophic factor, tumour necrosis factor-alpha and alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) regulate synaptic scaling in the AD brain. It is suggested that further studies on synaptic scaling in AD could reveal new targets for therapeutic drug development.

Curcumin inhibits aggregation of α-synuclein

Aggregation of amyloid-beta protein (Abeta) is a key pathogenic event in Alzheimer's disease (AD). Curcumin, a constituent of the Indian spice Turmeric is structurally similar to Congo Red and has been demonstrated to bind Abeta amyloid and prevent further oligomerization of Abeta monomers onto growing amyloid beta-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid formation are similar in Parkinson's disease (PD) and AD, we investigated the effect of curcumin on alpha-synuclein (AS) protein aggregation. In vitro model of AS aggregation was developed by treatment of purified AS protein (wild-type) with 1 mM Fe3+ (Fenton reaction). It was observed that the addition of curcumin inhibited aggregation in a dose-dependent manner and increased AS solubility. The aggregation-inhibiting effect of curcumin was next investigated in cell culture utilizing catecholaminergic SH-SY5Y cell line. A model system was developed in which the red fluorescent protein (DsRed2) was fused with A53T mutant of AS and its aggregation examined under different concentrations of curcumin. To estimate aggregation in an unbiased manner, a protocol was developed in which the images were captured automatically through a high-throughput cell-based screening microscope. The obtained images were processed automatically for aggregates within a defined dimension of 1-6 microm. Greater than 32% decrease in mutant alpha-synuclein aggregation was observed within 48 h subsequent to curcumin addition. Our data suggest that curcumin inhibits AS oligomerization into higher molecular weight aggregates and therefore should be further explored as a potential therapeutic compound for PD and related disorders.

Interaction of transthyretin with amyloid beta-protein: binding and inhibition of amyloid formation.

Aggregated amyloid beta-protein (A beta) is a key component of the amyloid depositions found in the brains of patients with Alzheimer's disease. In contrast, in cerebrospinal fluid (CSF), A beta is found in a soluble form. The analysis of complexes of A beta with CSF proteins in a KBr gradient revealed an association of A beta only with free proteins and not with lipoprotein particles. Transthyretin (TTR), a second major CSF protein, formed SDS-stable complexes with A beta and significantly decreased the rate of A beta fibril formation. In physiological buffers and CSF, TTR exclusively decreased the level of A beta pentamers. Endogenous TTR-A beta complexes were detected in human CSF by immunoprecipitation. Using site-directed mutagenesis and computer-assisted modelling, we identified amino acid residues on the surface of the TTR monomer that interact with A beta. Specific TTR immunoreactivity was detected in multiple cortical neurons and astrocytes in the human brain. We propose that A beta binding proteins play a key role in the modulation of A beta aggregation and normally prevent amyloid formation in biological fluids and in the brain.

Mechanisms of amyloid plaque pathogenesis

The first ultrastructural investigations of Alzheimer's disease noted the prominence of degenerating mitochondria in the dystrophic neurites of amyloid plaques, and speculated that this degeneration might be a major contributor to plaque pathogenesis. However, the fate of these organelles has received scant consideration in the intervening decades. A number of hypotheses for the formation and progression of amyloid plaques have since been suggested, including glial secretion of amyloid, somal and synaptic secretion of amyloid-beta protein from neurons, and endosomal-lysosomal aggregation of amyloid-beta protein in the cell bodies of neurons, but none of these hypotheses fully account for the focal accumulation of amyloid in plaques. In addition to Alzheimer's disease, amyloid plaques occur in a variety of conditions, and these conditions are all accompanied by dystrophic neurites characteristic of disrupted axonal transport. The disruption of axonal transport results in the autophagocytosis of mitochondria without normal lysosomal degradation, and recent evidence from aging, traumatic injury, Alzheimer's disease and transgenic mice models of Alzheimer's disease, suggests that the degeneration of these autophagosomes may lead to amyloid production within dystrophic neurites. The theory of amyloid plaque pathogenesis has thus come full circle, back to the intuitions of the very first researchers in the field.

Low‐density lipoprotein receptor‐related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway

The major defining pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid beta protein (Abeta), a small peptide derived from beta- and gamma-secretase cleavages of the amyloid precursor protein (APP). Recent studies have shown that beta- and gamma-secretase activities of BACE1 and presenilin, respectively, are concentrated in intracellular lipid raft microdomains. However, the manner in which APP normally traffics to lipid rafts is unknown. In this study, using transient transfection and immuno-precipitation assays, we show that the cytoplasmic domain of low-density lipoprotein receptor-related protein (LRP) interacts with APP and increases Abeta secretion and APP beta-CTF (C-terminal fragment) generation by promoting BACE1-APP interaction. We also employed discontinuous sucrose density gradient ultracentrifugation to show that the LRP cytoplasmic domain-mediated effect was accompanied by greatly increased localization of APP and BACE1 to lipid raft membranes, where beta- and gamma-secretase activities are highly enriched. Moreover, we provide evidence that endogenous LRP is required for the normal delivery of APP to lipid rafts and Abeta generation primarily in the endocytic but not secretory pathway. These results may provide novel insights to block Abeta generation by targeting LRP-mediated delivery of APP to raft microdomains.

Plasma Aβ Levels Do Not Reflect Brain Aβ Levels

Cerebral accumulation of amyloid beta protein (Abeta) is characteristic of Alzheimer disease (AD). Abeta can be detected in cerebrospinal fluid and in plasma. Although plasma Abeta has been proposed as a marker of risk of AD, it is unknown how plasma levels relate to neuropathologic levels. We compared plasma levels of Abeta40 and Abeta42 obtained during life with biochemical and pathologic levels in frontal and temporal neocortex in 25 individuals (17 AD, 3 control, and 5 non-AD dementia) who died a median of 1 year after blood collection. Plasma levels of Abeta40 and Abeta42 were not associated with any of the brain measures, even after adjusting for age and interval between plasma collection and death. The APOE epsilon4 allele may modify the relationship between plasma Abeta42 and formic acid-extractable Abeta42, with an inverse correlation in APOE epsilon4 carriers and a positive correlation in those lacking APOE epsilon4. We conclude that plasma levels of Abeta40 and Abeta42 are not robust correlates of histologic or biochemically assessed amyloid burdens in brain, although the influence of the APOE genotype should be further explored.

Possible role of scavenger receptor SRCL in the clearance of amyloid‐βin Alzheimer's disease

Accumulation of beta-amyloid protein (Abeta) in the brain is a hallmark of Alzheimer's disease (AD), and Abeta-mediated pathogenesis could result from increased production of Abeta or insufficient Abeta clearance by microglia, astrocytes, or the vascular system. Cell-surface receptors, such as scavenger receptors, might play a critical role in the binding and clearing of Abeta; however, the responsible receptors have yet to be identified. We show that scavenger receptor with C-type lectin (SRCL), a member of the scavenger receptor family containing coiled-coil, collagen-like, and C-type lectin/carbohydrate recognition domains, is expressed in cultured astrocytes and microglia. In contrast to the low expression of SRCL in the wild-type mouse brain, in a double transgenic mouse model of AD (Tg-APP/PS1), immunohistochemistry showed that SRCL was markedly induced in Abeta-positive astrocytes and Abeta-positive vascular/perivascular cells, which are associated closely with cerebral amyloid angiopathy. In patients with AD, the distribution of SRCL was similar to that seen in the Tg-APP/PS1 temporal cortex. The presence of a large number of SRCL/Abeta double-positive particles in the intracellular compartments of reactive astrocytes and vascular/perivascular cells in Tg-APP/PS1 mice and AD patients suggests a role for SRCL in Abeta clearance. Moreover, CHO-K1 cells transfected with SRCL isoforms were found to bind fibrillar Abeta(1-42). These findings suggest that SRCL could be the receptor involved in the binding or clearing of Abeta by glial and vascular/perivascular cells in AD.

Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers.

The accumulation of amyloid beta-protein (Abeta) in brain regions serving memory and cognition is a central pathogenic feature of Alzheimer's disease (AD). We have shown that small soluble oligomers of human Abeta that are naturally secreted by cultured cells inhibit hippocampal long-term potentiation (LTP) in vitro and in vivo and transiently impair the recall of a complex learned behaviour in rats. These results support the hypothesis that diffusible oligomers of Abeta initiate a synaptic dysfunction that may be an early event in AD. We now report detailed electrophysiological analyses that define conditions under which acute application of soluble Abeta inhibits hippocampal synaptic plasticity in wild-type mice. To ascertain which Abeta assemblies contribute to the impairment of LTP, we fractionated oligomers by size-exclusion chromatography and found that Abeta trimers fully inhibit LTP, whereas dimers and tetramers have an intermediate potency. Natural Abeta oligomers are sensitive to heat denaturation, primarily inhibit the induction phase of LTP, and cause a sustained impairment of LTP even after extensive washout. We observed no effects of Abeta oligomers on presynaptic vesicle release. LTP in juvenile mice is resistant to the effects of Abeta oligomers, as is brain-derived-neurotrophic-factor-induced LTP in adult hippocampus. We conclude that specific assemblies, particularly timers, of naturally secreted Abeta oligomers are potent and selective inhibitors of certain forms of hippocampal LTP.