Deposition Of Amyloid Beta-protein Research Articles

P2‐434: Aurin tricarboxylic acid may help Alzheimer's disease and other conditions by blocking the MAC of complement

Complement plays a vital role in host defense by recognizing a target, opsonizing it and directly killing cells through the membrane attack complex (MAC). This final function, which assembles C5b-9(n) on viable cell surfaces, inadvertently kills host cells in a spectrum of human disorders. These include Alzheimer disease, paroxysmal nocturnal hemoglobinemia, heart and other organ transplants, myasthenia gravis, age related macular degeneration, Parkinson disease, tauopathies, ALS, Pick disease, atherosclerosis, multiple sclerosis and type 2 diabetes. We show that aurin tricarboxylic acid (ATA) blocks the addition of C9 to C5b-8 so that the MAC cannot form. It should therefore be efficacious in these diseases. ATA (MW 422) was prepared by passing commercially obtained Aluminon through a 0.5 kDa filter. Serum from normal human, rat, mouse, dog and cat was assayed for blockade of complement activation by ATA in a standard complement hemolysis assay. The complement proteins attached to the red cells were analyzed by Western blotting. For testing of ATA efficacy in vivo, control and Alzheimer APP/PS1(5xFAD) mice were fed normal chow or chow supplemented with 100 mg/kg ATA. Feeding was started at ages from 56-63 days and they were maintained on these diets for a further 30 days or 48 days before sacrifice. Some mice were examined for memory retention in a standard water maze test. ATA inhibited human, mouse, rat, dog and cat complement-mediated red blood cell hemolysis in a concentration-dependent manner with IC 50 s in the nM range. Western blot analysis of the complement proteins attached to red cells showed that the opsonizing components of complement were the same in serum with and without ATA. However, the MAC was fully formed from normal serum, but was arrested at the C5b678 stage in ATA treated serum. APP/PS1(5xFAD) mice develop early memory deficits due to the rapid buildup of beta amyloid protein deposits. They had significantly better spatial memory than the non-treated mice. No ill effects were detected in these mice. ATA blocks formation of the MAC by preventing C9 from binding to C5b-8. It holds great promise as a new, broad spectrum therapeutic agent.

ApoE: The link between Alzheimer’s-related glucose hypometabolism and Aβ deposition?

Alzheimer’s disease (AD) is a complex, multifactorial progressive neurodegenerative disease. Pathologically, AD is characterized by extracellular deposits of amyloid beta (Aβ) protein and intracellular accumulation of neurofibrillary tangles (NFTs) of tau. The central role of Aβ protein in the AD etiology is well-established, and its increased deposition in AD brain is attributed to its decreased clearance from the brain. It is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for late-onset AD, has been shown to play a vital role in brain Aβ clearance and the ability of ApoE to do this depends mainly upon its lipidation status. Thus, lower ApoE lipidation status leading to decreased Aβ clearance may underlie the increased Aβ deposition observed in AD brain. In addition to the pathophysiological Aβ deposits, AD is also characterized by certain metabolic changes. Among them, decreased cerebral glucose metabolism is one of the distinct characteristics of AD brain and is also observed in patients with Mild Cognitive Impairment (MCI) who subsequently develop AD. Thus, decreased cerebral glucose metabolism is an early event in AD pathology and may precede the neuropathological Aβ deposition associated with AD. In this context, we hypothesize here that the decreased glucose metabolism in pre-AD and early AD stages, may lead to lower ApoE lipidation status, which in turn may lead to decreased clearance and hence, increased deposition of Aβ protein in AD brain.

Primate aging in the mammalian scheme: the puzzle of extreme variation in brain aging.

At later ages, humans have high risk of developing Alzheimer disease (AD) which may afflict up to 50% by 90 years. While prosimians and monkeys show more substantial changes, the great apes brains examined show mild neurodegenerative changes. Compared with rodents, primates develop and reproduce slowly and are long lived. The New World primates contain some of the shortest as well as some of the longest-lived monkey species, while the prosimians develop the most rapidly and are the shortest lived. Great apes have the largest brains, slowest development, and longest lives among the primates. All primates share some level of slowly progressive, age-related neurodegenerative changes. However, no species besides humans has yet shown regular drastic neuron loss or cognitive decline approaching clinical grade AD. Several primates accumulate extensive deposits of diffuse amyloid-beta protein (Aβ) but only a prosimian-the gray mouse lemur-regularly develops a tauopathy approaching the neurofibrillary tangles of AD. Compared with monkeys, nonhuman great apes display even milder brain-aging changes, a deeply puzzling observation. The genetic basis for these major species differences in brain aging remains obscure but does not involve the Aβ coding sequence which is identical in nonhuman primates and humans. While chimpanzees merit more study, we note the value of smaller, shorter-lived species such as marmosets and small lemurs for aging studies. A continuing concern for all aging studies employing primates is that relative to laboratory rodents, primate husbandry is in a relatively primitive state, and better husbandry to control infections and obesity is needed for brain aging research.

Vaccine Development to Treat Alzheimer’s Disease Neuropathology in APP/PS1 Transgenic Mice

A novel vaccine addressing the major hallmarks of Alzheimer's disease (AD), senile plaque-like deposits of amyloid beta-protein (Aβ), neurofibrillary tangle-like structures, and glial proinflammatory cytokines, has been developed. The present vaccine takes a new approach to circumvent failures of previous ones tested in mice and humans, including the Elan-Wyeth vaccine (AN1792), which caused massive T-cell activation, resulting in a meningoencephalitis-like reaction. The EB101 vaccine consists of Aβ 1-42 delivered in a novel immunogen-adjuvant composed of liposomes-containing sphingosine-1-phosphate (S1P). EB101 was administered to APPswe/PS1dE9 transgenic mice before and after AD-like pathological symptoms were detectable. Treatment with EB101 results in a marked reduction of Aβ plaque burden, decrease of neurofibrillary tangle-like structure density, and attenuation of astrocytosis. In this transgenic mouse model, EB101 reduces the basal immunological interaction between the T cells and immune activation markers in the affected hippocampal/cortical areas, consistent with decreased amyloidosis-induced inflammation. Therefore, immunization with EB101 prevents and reverses AD-like neuropathology in a significant manner by halting disease progression without developing behavioral spatial deficits in transgenic mice.

S14G-Humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by clinical cognitive decline and pathological deposition of amyloid-beta protein (Aβ) in the brain. So far, there has been no causative therapy for this devastating disease. S14G-Humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to have strong neuroprotective ability against AD-related insults in vitro and prevent cognitive impairments in Aβ-infused animal models. In addition, a recent study has reported a beneficial effect of intranasal HNG treatment on memory deficit and Aβ accumulation in triple transgenic (3xTg-AD) mice at the early plaque-bearing stage. However, whether HNG treatment has the disease-modifying efficacy on AD with pre-existing well-established amyloid plaque pathology remains unclear. In this study, we employed 9-month-old APPswe/PS1dE9 mice with pre-existing robust amyloid plaque pathology to investigate the effects of chronic HNG treatment on the progression of cognitive dysfunction and Aβ-associated neuropathology. We found that vehicle-treated APPswe/PS1dE9 mice showed impaired spatial learning and memory compared with vehicle- and HNG-treated wild-type mice, while intraperitoneal HNG treatment for 3months significantly improved spatial learning and memory deficits in APPswe/PS1dE9 mice compared with vehicle control treatment. Coincidental with this, HNG treatment significantly reduced cerebral Aβ plaque deposition, insoluble Aβ levels, and neuroinflammatory responses in APPswe/PS1dE9 mice compared with control treatment. Cumulatively, these findings demonstrate that chronic administration of HNG is able to attenuate cognitive deficits and reduce Aβ loads as well as neuroinflammation in the middle-aged APPswe/PS1dE9 mice even with pre-existing substantial Aβ neuropathology, indicating that HNG has potential as a pharmacotherapeutic intervention in the development of cognitive deficits and neuropathology seen in the cases of established AD.

β-Amyloid protein (Aβ) and human amylin regulation of apoptotic genes occurs through the amylin receptor

Deposition of amyloid-beta (Aβ) protein, a 39-43 amino acid peptide, in the brain is a major pathological feature of Alzheimer's disease (AD). We have previously provided evidence that in primary cultures of rat basal forebrain and human fetal neurons (HFNs), neurotoxic effects of oligomeric Aβ are expressed through the amylin receptor. In this study, we utilized RT-PCR arrays to compare RNA expression levels of 84 markers for pro and anti- apoptotic signalling pathways following exposure of HFNs to either Aβ(1-42) (20μM) or human amylin (2μM). Oligomeric Aβ(1-42) or human amylin was applied to HFNs alone or after pre-treatment of cultures with the amylin receptor antagonist, AC253. Changes in RNA levels were then quantified and compared to each other in order to identify increases or decreases in gene expression of apoptotic markers. Applications of Aβ(1-42) or human amylin, but not the inactive inverse sequence Aβ(42-1) or rat amylin, resulted in a time-dependent marked increase in mediators of apoptosis including a 10- to 30-fold elevations in caspases 3, 6, 9, BID and XIAP levels. Amylin receptor antagonists, AC253 (10μM) or AC187 (10μM), significantly attenuated the induction of several pro-apoptotic mediators up-regulated following exposure to Aβ(1-42) or human amylin and increased the expression of several anti-apoptotic markers. These data allow us to identify key elements in the Aβ-induced apoptosis that are blocked by antagonism of the amylin receptor and further support the potential for amylin receptor blockade as a potential therapeutic avenue in AD.

Genetic association of TLR4/11367 polymorphism with late-onset Alzheimer's disease in a Han Chinese population

The amyloid beta-protein (A-β) deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses that were assumed to play a pivotal role in the pathogenesis of AD. Toll-like receptor 4 (TLR4) is thought to contribute to Aβ clearance. Studies have reported the presence and functional significance of the TLR4/11367 polymorphism in a Han Chinese population. To evaluate the involvement of the TLR4/11367 polymorphism in the risk of late-onset Alzheimer's disease (LOAD), we performed a case–control study to analyze the genotype and allele distributions of the TLR4/11367 polymorphism in a Han Chinese population (137 LOAD cases and 137 healthy controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P<0.001, allele P<0.001). After stratification by APOE ε4-carrying status, the C allele of the TLR4/11367 polymorphism was still significantly associated with LOAD in APOE ε4 non-carriers (OR=5.77, 95% CI=3.03–11.00, P<0.001) and carriers (OR=2.03, 95% CI=1.03–3.98, P=0.04). In addition, a logistic regression analysis also conferred positive association between TLR4/11367C and LOAD (dominant model: ORa=3.08, 95% CI=1.60–5.93, P=0.001; recessive model: ORa=8.79, 95% CI=3.31–23.36, P<0.001; additive model: ORa=2.75, 95% CI=1.73–4.37, P<0.001) after adjustment for age, gender, and the APOE ε4 carrier status. This study gives the first evidence that the TLR4/11367 polymorphism was associated with LOAD in a Han Chinese population.

Association between late-onset Alzheimer's disease and microsatellite polymorphisms in intron II of the human toll-like receptor 2 gene

The amyloid beta protein (Aβ) deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses that were assumed to play a pivotal role in the pathogenesis of AD. Toll-like receptor 2 (TLR2) is thought to contribute to Aβ clearance. Studies have reported the presence and functional implications of guanine-thymine (GT) repeat microsatellite polymorphisms in intron II of the human TLR2 gene. The present study evaluated the association of the microsatellite polymorphism and sporadic late-onset AD (LOAD) in the Han Chinese population. The numbers of (GT) repeats were counted in 137 AD patients and in 137 non-AD control subjects, using polymerase chain reaction and genescan analysis. The alleles were divided into three subclasses: (GT)16 or less as the S allele, (GT)17 to (GT)22 as the M allele, and (GT)23 or more as the L allele. Patients with AD had more S alleles ( P < 0.001; odds ratio (OR) = 2.32; 95% confidence interval (CI) = 1.57–3.42) and fewer L alleles ( P = 0.02; OR = 0.66; 95% CI = 0.46–0.93) than did healthy controls. Genotypes SS and SM were more common, whereas ML and SL were less common in patients with AD. In subgroup analyses, the genotypes including S alleles were associated with an increased risk of LOAD (OR = 2.05, 95% CI = 1.26–3.34), and this association was influenced by the presence of APOE ɛ4 alleles. This study demonstrates an association of microsatellite polymorphisms in intron II of the human TLR2 gene with risk for LOAD in Han Chinese.

Characterizing amyloid‐beta protein misfolding from molecular dynamics simulations with explicit water

Extracellular deposition of amyloid-beta (Aβ) protein, a fragment of membrane glycoprotein called β-amyloid precursor transmembrane protein (βAPP), is the major characteristic for the Alzheimer's disease (AD). However, the structural and mechanistic information of forming Aβ protein aggregates in a lag phase in cell exterior has been still limited. Here, we have performed multiple all-atom molecular dynamics simulations for physiological 42-residue amyloid-beta protein (Aβ42) in explicit water to characterize most plausible aggregation-prone structure (APS) for the monomer and the very early conformational transitions for Aβ42 protein misfolding process in a lag phase. Monitoring the early sequential conformational transitions of Aβ42 misfolding in water, the APS for Aβ42 monomer is characterized by the observed correlation between the nonlocal backbone H-bond formation and the hydrophobic side-chain exposure. Characteristics on the nature of the APS of Aβ42 allow us to provide new insight into the higher aggregation propensity of Aβ42 over Aβ40, which is in agreement with the experiments. On the basis of the structural features of APS, we propose a plausible aggregation mechanism from APS of Aβ42 to form fibril. The structural and mechanistic observations based on these simulations agree with the recent NMR experiments and provide the driving force and structural origin for the Aβ42 aggregation process to cause AD.

Incidence and Severity of Deposition of Amyloid beta Protein in the Precuneus and the Posterior Cingulate Gyrus in An Aging Cohort

Incidence and Severity of Deposition of Amyloid beta Protein in the Precuneus and the Posterior Cingulate Gyrus in An Aging Cohort

Gelsolin, a beta amyloid-binding protein is proteolytically cleaved in the brains of Alzheimer's disease and in adults with down syndrome

The deposition of fibrillar amyloid beta-protein (Aβ) is one of the main events in the amyloid plaques formation in Alzheimer's disease (AD) and adult Down syndrome (DS) individuals. Accumulating evidence from our and other groups has shown that gelsolin, a cytoplasmic and secretory protein, regulates the fibrillogenesis of Aβ. Gelsolin is constitutively expressed through out the central nervous system, and it inhibits the fibrillization of Aβ, and defibrillizes the preformed Aβ fibrils. We studied whether there is a relationship between the levels of Aβ and gelsolin in the brains of AD and DS subjects. The homogenates of postmortem brain samples of frontal cortex from patients with AD (age 64-85 y, n = 8) and DS (age 43-63 y) and age-matched control subjects were prepared. Then homogenates were analyzed for gelsolin and its proteolytic fragment by Western blot. The levels of Aβ were measured in the homogenates by ELISA.. Our results showed the presence of a carboxyl-terminal gelsolin peptide (CTF-gelsolin), a proteolytically cleaved fragment of gelsolin, in the brain sample from AD but not in age-matched controls (n = 6). A correlation was observed between the levels of CTF-gelsolin and severity of the disease. Similarly, we observed that proteolysis of gelsolin also occurs in the brains of adult DS (n = 7) but not in age-matched control (n = 6) subjects. The levels of soluble Aβ40/Aβ42 were increased in the brains of adult patients with DS. A positive correlation was observed between the levels of soluble Aβ40/Aβ 42, and the proteolysis of gelsolin. We suggest that gelsolin cleavage in the brains may act as a marker of amyloid -mediated pathogenesis in AD and DS.

Aberrant Detergent-Insoluble Excitatory Amino Acid Transporter 2 Accumulates in Alzheimer Disease

Alzheimer disease (AD) is characterized by deposition of amyloid-beta, tau, and other specific proteins that accumulate in the brain in detergent-insoluble complexes. Alzheimer disease also involves glutamatergic neurotransmitter system disturbances. Excitatory amino acid transporter 2 (EAAT2) is the dominant glutamate transporter in cerebral cortex and hippocampus. We investigated whether accumulation of detergent-insoluble EAAT2 is related to cognitive impairment and neuropathologic changes in AD by quantifying detergent-insoluble EAAT2 levels in hippocampus and frontal cortex of cognitively normal patients, patients with clinical dementia rating of 0.5 (mildly impaired), and AD patients. Parkinson disease patients served as neurodegenerative disease controls. We found that Triton X-100-insoluble EAAT2 levels were significantly increased in patients with AD compared with controls, whereas Triton X-100-insoluble EAAT2 levels inpatients with clinical dementia rating of 0.5 were intermediately elevated between control and AD subjects. Detergent insolubility of presenilin-1, a structurally similar protein, did not differ among the groups, thus arguing that EAAT2 detergent insolubility was not caused by nonspecific cellular injury. These findings demonstrate that detergent-insoluble EAAT2 accumulation is a progressive biochemical lesion that correlates with cognitive impairment and neuropathologic changes in AD. These findings lend further support to the idea that dysregulation of the glutamatergic system may play a significant role in AD pathogenesis.

Withanolide A and asiatic acid modulate multiple targets associated with amyloid-beta precursor protein processing and amyloid-beta protein clearance.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease histochemically characterized by extracellular deposits of amyloid beta (Abeta) protein and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is considered to be a complex, multifactorial syndrome, with numerous causal factors contributing to its pathogenesis. Thus, for any novel therapeutic molecule to have a "disease-modifying" effect on AD, it must be able to modulate multiple, synergistic targets simultaneously. In this context, we have studied two compounds of plant origin [withanolide A (1) and asiatic acid (2)] for their potential activities against multiple targets associated with Abeta pathways (BACE1, ADAM10, IDE, and NEP). BACE1 is a rate-limiting enzyme in the production of Abeta from amyloid-beta precursor protein (AbetaPP), while ADAM10 is involved in non-amyloidogenic processing of AbetaPP. IDE and NEP are two of the prominent enzymes involved in effectively degrading Abeta. It was found that both 1 and 2 significantly down-regulated BACE1 and also up-regulated ADAM10 in primary rat cortical neurons. In addition, 1 significantly up-regulated IDE levels, which may help in degrading excess Abeta from the AD brain. On the basis of the data obtained, the two multifunctional compounds may prove valuable in developing novel, effective therapeutics for the prevention and treatment of AD-associated amyloid pathology.

Capillary cerebral amyloid angiopathy identifies a distinct APOE ε4-associated subtype of sporadic Alzheimer’s disease

The deposition of amyloid beta-protein (Abeta) in the vessel wall, i.e., cerebral amyloid angiopathy (CAA), is associated with Alzheimer's disease (AD). Two types of CAA can be differentiated by the presence or absence of capillary Abeta-deposits. In addition, as in Alzheimer's disease, risk for capillary CAA is associated with the apolipoprotein E (APOE) epsilon4-allele. Because these morphological and genetic differences between the two types of AD-related CAA exist, the question arises as to whether there exist further differences between AD cases with and without capillary CAA and, if so, whether capillary CAA can be employed to distinguish and define specific subtypes of AD. To address this question, we studied AD and control cases both with and without capillary CAA to identify the following: (1) distinguishing neuropathological features; (2) alterations in perivascular protein expression; and (3) genotype-specific associations. More widespread Abeta-plaque pathology was observed in AD cases with capillary CAA than in those without. Expression of perivascular excitatory amino acid transporter 2 (EAAT-2/GLT-1) was reduced in cortical astrocytes of AD cases with capillary CAA in contrast to those lacking capillary Abeta-deposition and controls. Genetically, AD cases with capillary CAA were strongly associated with the APOE epsilon4 allele compared to those lacking capillary CAA and to controls. To further validate the existence of distinct types of AD we analyzed polymorphisms in additional apoE- and cholesterol-related candidate genes. Our results revealed an association between AD cases without capillary CAA (i.e., AD cases with CAA but lacking capillary CAA and AD cases without CAA) and the T-allele of the alpha(2)macroglobulin receptor/low-density lipoprotein receptor-related protein-1 (LRP-1) C766T polymorphism as opposed to AD cases with capillary CAA and non-AD controls. Taken together, these results indicate that AD cases with capillary CAA differ significantly from other AD cases both genetically and morphologically, thereby pointing to a specific capillary CAA-related and APOE epsilon4-associated subtype of AD.

Amyloid-modifying therapies for Alzheimer’s disease: therapeutic progress and its implications

Alzheimer's disease (AD) is the most prevalent form of dementia, affecting an estimated 4.8 million people in North America. For the past decade, the amyloid cascade hypothesis has dominated the field of AD research. This theory posits that the deposition of amyloid-beta protein (Abeta) in the brain is the key pathologic event in AD, which induces a series of neuropathological changes that manifest as cognitive decline and eventual dementia. Based on this theory, interventions that reduce Abeta burden in the brain would be expected to alleviate both the neuropathological changes and dementia, which characterize AD. Several diverse pharmacological strategies have been developed to accomplish this. These include inhibiting the formation of Abeta, preventing the aggregation of Abeta into insoluble aggregates, preventing the entry of Abeta into the brain from the periphery and enhancing the clearance of Abeta from the central nervous system. To date, no amyloid-modifying therapy has yet been successful in phase 3 clinical trials; however, several trials are currently underway. This article provides a review of the status of amyloid-modifying therapies and the implications for the amyloid cascade hypothesis.

Neurobiology of cognitive disorders

Neurodegenerative brain diseases, including Alzheimer's disease, frontotemporal degeneration and Lewy body disease, are the most frequent pathologies underlying cognitive disorders in old age. This review outlines recent advances in the understanding of key molecular mechanisms involved in these neurodegenerations, particularly with regard to the abnormal processing of proteins. The consequences of these novel insights for therapeutic interventions are also explained. Aberrant processing, misfolding, and subsequent deposition of amyloid beta protein, TAU, alpha-synuclein, and TDP-43 are key events in the pathological cascades of neurodegenerations leading to cognitive impairment and dementia. The nonpolymerized, oligomeric forms of these proteins have neurotoxic properties including the disruption of synaptic function and the induction of oxidative stress. The aggregation and deposition of these proteins may represent a neuronal repair mechanism which ultimately worsens the deleterious effects of the preaggregated forms. Novel disease-modifying treatment strategies aim at down-regulating protein production, inhibiting polymerization, or removing preaggregated forms of the proteins from the brain. Recent research has elucidated important molecular events in neurodegenerative diseases upstream of the aggregation and deposition of proteins which forms their histopathological hallmarks. These insights translate into novel therapeutic strategies which are currently evaluated in clinical trials.

X11 rescues memory and long-term potentiation deficits in Alzheimer's disease APPswe Tg2576 mice

Increased production and deposition of amyloid beta-protein (Abeta) are believed to be key pathogenic events in Alzheimer's disease. As such, routes for lowering cerebral Abeta levels represent potential therapeutic targets for Alzheimer's disease. X11beta is a neuronal adaptor protein that binds to the intracellular domain of the amyloid precursor protein (APP). Overexpression of X11beta inhibits Abeta production in a number of experimental systems. However, whether these changes to APP processing and Abeta production induced by X11beta overexpression also induce beneficial effects to memory and synaptic plasticity are not known. We report here that X11beta-mediated reduction in cerebral Abeta is associated with normalization of both cognition and in vivo long-term potentiation in aged APPswe Tg2576 transgenic mice that model the amyloid pathology of Alzheimer's disease. Overexpression of X11beta itself has no detectable adverse effects upon mouse behaviour. These findings support the notion that modulation of X11beta function represents a therapeutic target for Abeta-mediated neuronal dysfunction in Alzheimer's disease.

Effects of Stress and Stress Hormones on Amyloid-β Protein and Plaque Deposition

Growing evidence indicates that physical and psychosocial stressors, in part acting through the hypothalamic-pituitary-adrenal (HPA) axis, may accelerate the process of Alzheimer's disease (AD). In this review, we summarize recent research related to the effects of stress and stress hormones on the various disease process elements associated with AD. Specifically, we focus on the relationships among chronic stressors, HPA axis activity, amyloid-beta protein, and amyloid-beta plaque deposition in mouse models of AD. The potential mechanisms by which stress and stress-related components, especially corticotrophin-releasing factor and its receptors, influence the pathogenesis of AD are discussed.

Amyloid Deposition Is Associated with Impaired Default Network Function in Older Persons without Dementia

Alzheimer's disease (AD) has been associated with functional alterations in a distributed network of brain regions linked to memory function, with a recent focus on the cortical regions collectively known as the default network. Posterior components of the default network, including the precuneus and posterior cingulate, are particularly vulnerable to early deposition of amyloid beta-protein, one of the hallmark pathologies of AD. In this study, we use in vivo amyloid imaging to demonstrate that high levels of amyloid deposition are associated with aberrant default network functional magnetic resonance imaging (fMRI) activity in asymptomatic and minimally impaired older individuals, similar to the pattern of dysfunction reported in AD patients. These findings suggest that amyloid pathology is linked to neural dysfunction in brain regions supporting memory function and provide support for the hypothesis that cognitively intact older individuals with evidence of amyloid pathology may be in early stages of AD.

Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease

The role of microglial cells in the pathogenesis of Alzheimer’s disease (AD) neurodegeneration is unknown. Although several works suggest that chronic neuroinflammation caused by activated microglia contributes to neurofibrillary degeneration, anti-inflammatory drugs do not prevent or reverse neuronal tau pathology. This raises the question if indeed microglial activation occurs in the human brain at sites of neurofibrillary degeneration. In view of the recent work demonstrating presence of dystrophic (senescent) microglia in aged human brain, the purpose of this study was to investigate microglial cells in situ and at high resolution in the immediate vicinity of tau-positive structures in order to determine conclusively whether degenerating neuronal structures are associated with activated or with dystrophic microglia. We used a newly optimized immunohistochemical method for visualizing microglial cells in human archival brain together with Braak staging of neurofibrillary pathology to ascertain the morphology of microglia in the vicinity of tau-positive structures. We now report histopathological findings from 19 humans covering the spectrum from none to severe AD pathology, including patients with Down’s syndrome, showing that degenerating neuronal structures positive for tau (neuropil threads, neurofibrillary tangles, neuritic plaques) are invariably colocalized with severely dystrophic (fragmented) rather than with activated microglial cells. Using Braak staging of Alzheimer neuropathology we demonstrate that microglial dystrophy precedes the spread of tau pathology. Deposits of amyloid-beta protein (Aβ) devoid of tau-positive structures were found to be colocalized with non-activated, ramified microglia, suggesting that Aβ does not trigger microglial activation. Our findings also indicate that when microglial activation does occur in the absence of an identifiable acute central nervous system insult, it is likely to be the result of systemic infectious disease. The findings reported here strongly argue against the hypothesis that neuroinflammatory changes contribute to AD dementia. Instead, they offer an alternative hypothesis of AD pathogenesis that takes into consideration: (1) the notion that microglia are neuron-supporting cells and neuroprotective; (2) the fact that development of non-familial, sporadic AD is inextricably linked to aging. They support the idea that progressive, aging-related microglial degeneration and loss of microglial neuroprotection rather than induction of microglial activation contributes to the onset of sporadic Alzheimer’s disease. The results have far-reaching implications in terms of reevaluating current treatment approaches towards AD.