Distinguishing visuospatial working memory and complex mental calculation areas within the parietal lobes

Our recent study has provided evidence that Abeta42, a 42 amino acid fragment of the amyloid precursor protein, accumulates intracellularly in vulnerable neurons. This study appears to show that neurons lyse and form dense-core amyloid plaques in Alzheimer's disease (AD) entorhinal cortex. Previous studies have suggested that intracellular Abeta42 co-localizes with lipofuscin in neurons and those increased levels of lipofuscin and Abeta42 are associated with AD. Other studies have questioned this relationship and suggested that beta-amyloid and lipofuscin are not co-localized and that their levels are independent of one another in AD and age-matched control tissues. In an effort to resolve this controversy, we investigated the relative spatial relationship of intracellular Abeta42 and lipofuscin in AD brains tissue using a novel combined immunohistochemical:histochemical staining protocol. Our results show separate and distinct localization patterns of Abeta42 and lipofuscin in neurons and amyloid plaques.     

Amyloid angiopathy and variability in amyloid beta deposition is determined by mutation position in presenilin-1-linked Alzheimer's disease

The presenilins (PSs) are components of large molecular complexes that contain beta-catenin and function as gamma-secretase. We report here a striking correlation between amyloid angiopathy and the location of mutation in PS-1 linked Alzheimer's disease. The amount of amyloid beta protein, Abeta(42(43)), but not Abeta(40,) deposited in the frontal cortex of the brain is increased in 54 cases of early-onset familial Alzheimer's disease, encompassing 25 mutations in the presenilin-1 (PS-1) gene, compared to sporadic Alzheimer's disease. The amount of Abeta(40) in PS-1 Alzheimer's disease varied according to the copy number of epsilon4 alleles of the Apolipoprotein E gene. Although the amounts of Abeta(40) and Abeta(42(43)) deposited did not correlate with the genetic location of the mutation in a strict linear sense, the histological profile did so vary. Cases with mutations between codon 1 and 200 showed, in frontal cortex, many diffuse plaques, few cored plaques, and mild or moderate amyloid angiopathy. Cases with mutations occurring after codon 200 also showed many diffuse plaques, but the number and size of cored plaques were increased (even when epsilon4 allele was not present) and these were often clustered around blood vessels severely affected by amyloid angiopathy. Similarly, diverging histological profiles, mainly according to the degree of amyloid angiopathy, were seen in the cerebellum. Mutations in the PS-1 gene may therefore alter the topology of the PS-1 protein so as to favor Abeta formation and deposition, generally, but also to facilitate amyloid angiopathy particularly in cases in which the mutation lies beyond codon 200. Finally we report that the amount of Abeta(42(43)) deposited in the brain correlated with the amount of this produced in culture by cells bearing the equivalent mutations.     

Co-localization of amyloid beta and tau pathology in Alzheimer's disease synaptosomes

The amyloid cascade hypothesis proposes that amyloid beta (Abeta) pathology precedes and induces tau pathology, but the neuropathological connection between these two lesions has not been demonstrated. We examined the regional distribution and co-localization of Abeta and phosphorylated tau (p-tau) in synaptic terminals of Alzheimer's disease brains. To quantitatively examine large populations of individual synaptic terminals, flow cytometry was used to analyze synaptosomes prepared from cryopreserved Alzheimer's disease tissue. An average 68.4% of synaptic terminals in the Alzheimer's disease cohort (n = 11) were positive for Abeta, and 32.3% were positive for p-tau; Abeta and p-tau fluorescence was lowest in cerebellum. In contrast to synaptic p-tau, which was highest in the entorhinal cortex and hippocampus (P = 0.004), synaptic Abeta fluorescence was significantly lower in the entorhinal cortex and hippocampus relative to neocortical regions (P = 0.0003). Synaptic Abeta and p-tau fluorescence was significantly correlated (r = 0.683, P < 0.004), and dual-labeling experiments demonstrated that 24.1% of Abeta-positive terminals were also positive for p-tau, with the highest fraction of dual labeling (39.3%) in the earliest affected region, the entorhinal cortex. Western blotting experiments show a significant correlation between synaptic Abeta levels measured by flow cytometry and oligomeric Abeta species (P < 0.0001). These results showing overlapping Abeta and tau pathology are consistent with a model in which both synaptic loss and dysfunction are linked to a synaptic amyloid cascade within the synaptic compartment.     

Mostly separate distributions of CLAC- versus Abeta40- or thioflavin S-reactivities in senile plaques reveal two distinct subpopulations of beta-amyloid deposits

Collagenous Alzheimer amyloid plaque component (CLAC) is a unique non-Abeta amyloid component of senile plaques (SP) derived from a transmembrane collagen termed CLAC-precursor. Here we characterize the chronological and spatial relationship of CLAC with other features of SP amyloid in the brains of patients with Alzheimer's disease (AD), Down syndrome (DS), and of PSAPP transgenic mice. In AD and DS cerebral cortex, CLAC invariably colocalized with Abeta42 but often lacked Abeta40- or thioflavin S (thioS)-reactivities. Immunoelectron microscopy of CLAC-positive SP showed labeling of fibrils that are more loosely dispersed compared to typical amyloid fibrils in CLAC-negative SP. In DS cerebral cortex, diffuse plaques in young patients were negative for CLAC, whereas a subset of SP became CLAC-positive in patients aged 35 to 50 years, before the appearance of Abeta40. In DS cases over 50 years of age, Abeta40-positive SP dramatically increased, whereas CLAC burden remained at a constant level. In PSAPP transgenic mice, CLAC was positive in the diffuse Abeta deposits surrounding huge-cored plaques. Thus, CLAC and Abeta40 or thioS exhibit mostly separate distribution patterns in SP, suggesting that CLAC is a relatively early component of SP in human brains that may have inhibitory effects against the maturation of SP into beta-sheet-rich amyloid deposits.     

Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid beta-protein precursor transgenic mice

Cerebral microvascular amyloid beta protein (Abeta) deposition and associated neuroinflammation are increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease and related cerebral amyloid angiopathy (CAA) disorders. Transgenic mice expressing the vasculotropic Dutch/Iowa (E693Q/D694N) mutant human Abeta precursor protein in brain (Tg-SwDI) accumulate abundant cerebral microvascular fibrillar amyloid deposits exhibiting robust neuroinflammation. In the present study, we sought to determine if the unique amyloid pathology of Tg-SwDI mice was associated with deficits in behavioral performance. Behavioral performance tests that assessed a variety of psychological functions, including overall activity, motor ability, balance and strength, anxiety, impulsivity, and learning were conducted on homozygous Tg-SwDI mice and similarly aged wild-type C57Bl/6 mice. Our results indicate that Tg-SwDI mice were impaired in the performance of the Barnes maze learning and memory task at 3, 9, and 12 months of age. While more widespread cerebral microvascular Abeta pathology was evident in older animals, the evaluation of the Abeta pathology in the 3 months old transgenic animals revealed specific accumulation of microvascular amyloid and markedly elevated numbers of reactive astrocytes and activated microglia restricted to the subiculum. These findings indicate that early-onset accumulation of subicular microvascular amyloid and accompanying neuroinflammation correlates with impaired performance in the learning and memory task in Tg-SwDI mice.     

Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe/PS1δE9-deleted transgenic mice model of ß-amyloidosis

Alzheimer's disease (AD) is characterized by progressive memory impairment and the formation of amyloid plaques in the brain. Dysfunctional excitatory synaptic transmission and synaptic plasticity are generally accepted as primary events in the development of AD, and beta-amyloid is intimately involved. Here we describe age related differences in learning, memory, synaptic transmission and long-term potentiation (LTP) in wild type and APPswe/PS1DeltaE9 mice, which produce increasing amounts of Abeta1-42 with age. The mice have both age related and age-independent deficits in radial arm water maze performance. Blind studies of hippocampal slices from transgenic and wild type mice demonstrate that transgenic mice have impaired transient LTP and that the degree of impairment is not related to age from 3 to 12 months. The deficiencies in transient LTP may be related to the behavioral deficits that did not progress with age. The accumulation of beta-amyloid and the episodic memory deficits, both of which increased with age, were not accompanied by an alteration in synaptic transmission or sustained LTP in the in vitro hippocampal slices.     

Time-course and regional analyses of the physiopathological changes induced after cerebral injection of an amyloid β fragment in rats

Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid β protein (Aβ) formed by pathological processing of the Aβ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated Aβ fragment 25-35 (Aβ(25-35)) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled Aβ(25-35) peptide was used as negative control. The aggregated forms of Aβ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of Aβ(25-35) decreased body weight, induced short- and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, Aβ(25-35), the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. In conclusion, the acute intracerebroventricular Aβ(25-35) injection induced substantial central modifications in rats, highly reminiscent of the human physiopathology, that could contribute to physiological and cognitive deficits observed in AD.     

Diffuse amyloid deposition,but not plaque number,is reduced in amyloid precursor protein/presenilin 1 double-transgenic mice by pathway lesions

Alzheimer's disease (AD) is the most common form of dementia in the elderly, and the characteristic pathological hallmarks of the disease are neuritic plaques and neurofibrillary tangles. The sequence of events leading to the extracellular deposition of amyloidbeta (Abeta) peptides in plaques or in diffuse deposits is not clear. Here we investigate the relation between disrupted axonal transport of amyloid precursor protein (APP) and/or Abeta and the deposition of Abeta in the deafferented terminal fields in APP/presenilin 1 double-transgenic AD-model mice. In the first experiment we ablated entorhinal cortex neurons and examined the subsequent changes in amyloid deposition in the hippocampus 1 month later. We show that there is a substantial reduction in the amount of diffuse amyloid deposits in the denervated areas of the hippocampus. Further, to investigate the effects of long-term deafferentation, in a second experiment we cut the fimbria-fornix and analyzed the brains 11 months post-lesion. Diffuse amyloid deposits in the deafferented terminal fields of area CA1 and subiculum were dramatically reduced as assessed by image analysis of the Abeta load. Our findings indicate that neuronal ablations decrease diffuse amyloid deposits in the terminal fields of these neurons, and, further, that pathway lesions similarly decrease the amount of diffuse amyloid deposits in the terminal fields of the lesioned axons. Together, this suggests that the axonal transport of APP and/or Abeta and subsequent secretion of Abeta at terminals plays an important role in the deposition of Abeta protein in Alzheimer's disease, and, further, that diffuse deposits do not develop into plaques.py>     

Cycloxygenase-2 activity promotes cognitive deficits but not increased amyloid burden in a model of Alzheimer's disease in a sex-dimorphic pattern

Administration of non-steroidal anti-inflammatory agents reduces the risk of developing Alzheimer's disease in normal aging populations, an effect that may occur from inhibition of the cyclooxygenases, the rate-limiting enzymes in the formation of prostaglandins. In this study, we investigated whether increased activity of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, potentiates disease progression in a transgenic mouse model of Alzheimer's disease. To study the functional effects of COX-2 activity, male and female bigenic mice (amyloid precursor protein with Swedish mutation [APPswe]-presenilin-1 protein with deletion of exon 9 [PS1dE9] and trigenic COX-2/APPswe-PS1dE9) were behaviorally tested +/-administration of the selective COX-2 inhibitor celecoxib. Behavioral testing included a three-trial Y maze that measures spatial working and recognition memories and an open field task that tested levels of hyperactivity. Overexpression of COX-2 in APPswe-PS1dE9 mice resulted in specific deficits in spatial working memory in female but not male mice. These sex-specific deficits were abolished by pharmacological inhibition of COX-2 activity. Importantly, COX-2-associated deficits were dependent on co-expression of all three transgenes since COX-2 single transgenic and APPswe-PS1dE9 bigenic mice showed normal memory. Quantification of amyloid plaque load and total Abeta 40 and 42 peptides did not reveal significant differences in trigenic versus bigenic mice treated with either vehicle or celecoxib. Taken together, these data indicate an interaction between the effects of COX-2 and Abeta peptides on cognition that occurs in a sex-specific manner in the absence of significant changes in amyloid burden. These findings suggest that pathological activation of COX-2 may potentiate the toxicity of Abeta peptides, particularly in females, without significantly affecting Abeta accumulation.     

Amyloid beta-peptide1-42 alters tight junction protein distribution and expression in brain microvessel endothelial cells

Alzheimer's disease is characterised by neuronal loss, numerous intraneuronal deposits of neurofibrillary tangles, senile plaques, and cerebrovascular amyloid deposits. The major component of senile plaques and cerebrovascular deposits is the 39-43 amino acid beta-amyloid peptide (Abeta). The effects of Abeta on cerebral endothelium and thus the blood-brain barrier remain unclear. Utilising endothelial cells isolated from rat cerebral cortex microvessels, we have examined effects of Abeta peptides on tight junction protein behaviour. The transmembrane tight junction proteins occludin, claudin-1 and claudin-5, as well as the cytoplasmic accessory proteins ZO-1 and ZO-2 displayed a continuous distribution at cell boundaries. Endothelial cells exposed to Abeta1-42 (20 microM) for 3 days showed a disrupted plasma membrane pattern of claudin-5 and ZO-2 with relocation to the cytoplasm. These effects were not seen with Abeta25-35 or Abeta1-40[Gln22] (Dutch type). Abeta1-42 treatment altered also protein expression: occludin was lower at 1st day, claudin-1 increased at all times, and ZO-2 increased after 1 day and then decreased. These data suggest that Abeta1-42 effects on tight junction protein complexes may alter blood-brain barrier integrity and contribute to the neuropathological sequelae of Alzheimer's disease.     

Object recognition memory and BDNF expression are reduced in young TgCRND8 mice

The TgCRND8 mouse model of Alzheimer's disease exhibits progressive cortical and hippocampal β-amyloid accumulation, resulting in plaque pathology and spatial memory impairment by 3 months of age. We tested whether TgCRND8 cognitive function is disrupted prior to the appearance of macroscopic plaques in an object recognition task. We found profound deficits in 8-week-old mice. Animals this age were not impaired on the Morris water maze task. TgCRND8 and littermate controls did not differ in their duration of object exploration or optokinetic responses. Thus, visual and motor dysfunction did not confound the phenotype. Object memory deficits point to the frontal cortex and hippocampus as early targets of functional disruption. Indeed, we observed altered levels of brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) in these brain regions of preplaque TgCRND8 mice. Our findings suggest that object recognition provides an early index of cognitive impairment associated with amyloid exposure and reduced brain-derived neurotrophic factor expression in the TgCRND8 mouse.     

CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid beta-peptide

Although deposition of amyloid beta-peptide (Abeta) as Abeta plaques involves activation of microglia-mediated inflammatory responses, activated microglia ultimately fail to clear Abeta plaques in the brains of either Alzheimer's disease (AD) patients or AD mouse models. Mounting evidence suggests that chronic microglia-mediated immune response during Abeta deposition etiologically contributes to AD pathogenesis by promoting Abeta plaque formation. However, the mechanisms that govern microglia response in the context of cerebral Abeta/beta-amyloid pathology are not well understood. We show that ligation of CD40 by CD40L modulates Abeta-induced innate immune responses in microglia, including decreased microglia phagocytosis of exogenous Abeta(1-42) and increased production of pro-inflammatory cytokines. CD40 ligation in the presence of Abeta(1-42) leads to adaptive activation of microglia, as evidenced by increased co-localization of MHC class II with Abeta. To assess their antigen-presenting cell (APC) function, cultured microglia were pulsed with Abeta(1-42) in the presence of CD40L and co-cultured with CD4(+) T cells. Under these conditions, microglia stimulate T cell-derived IFN-gamma and IL-2 production, suggesting that CD40 signaling promotes the APC phenotype. These data provide a mechanistic explanation for our previous work showing decreased microgliosis associated with diminished cerebral Abeta/beta-amyloid pathology when blocking CD40 signaling in transgenic Alzheimer's mice.     

Selective binding of soluble Abeta1-40 and Abeta1-42 to a subset of senile plaques.

Alzheimer's disease is characterized by the progressive accumulation of amyloid-beta protein (Abeta) in senile plaques and cerebral amyloid angiopathy. It is not known whether the plaque growth is a continuous and homogeneous process or whether some plaques have a more rapid evolution. As plaques grow by the deposition of Abeta, we used an in situ binding technique to analyze the deposition of fluorescein-conjugated and biotinylated Abeta1 40 and Abeta1-42 in cryosections of brains from Alzheimer's disease patients. Only a subset of senile plaques but all cerebrovascular Abeta deposits were labeled by both Abeta1-40 and Abeta1-42. Striking differences in binding were observed among adjacent plaques. Quantitative analysis showed that on average 60% of all plaques were labeled with Abeta1-42 and 31% of all plaques were labeled with Abeta1-40 (n=7; P<0.001). Confocal laser scanning microscopy of double-labeled sections revealed that the newly deposited Abeta was only partially co-localized to pre-existing Abeta and apolipoprotein E and was not co-localized to heparan sulfate proteoglycan. Abeta binding was preserved after glycolytic pretreatment with periodic acid. Our results suggest that at a given time point only a subset of active senile plaques accumulate A(beta) and that plaque growth may be conditioned by the presence of other distinct plaque components different from Abeta, apolipoprotein E or heparan sulfate proteoglycan.     

Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice

Transgenic mice with brain amyloid-beta (Abeta) plaques immunized with aggregated Abeta1-42 have reduced cerebral amyloid burden. However, the use of Abeta1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic Abeta homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% (P = 0.0002) and 81% (P = 0.0001), respectively. Concurrently, brain levels of soluble Abeta1-42 were reduced by 57% (P = 0.0019). Ramified microglia expressing interleukin-1beta associated with the Abeta plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic Abeta derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Abeta fibrils.     

Ultrastructural and behavioural changes precede amyloid deposition in a transgenic model of Alzheimer's disease

We describe the thorough characterisation of a new transgenic mouse line overexpressing the 695-amino acid isoform of human amyloid precursor protein harbouring the Swedish double familial Alzheimer's disease mutation. This line, referred to as TAS10, exhibits neuropathological features and cognitive deficits that are closely correlated to the accumulation of Abeta in their brain and that are reminiscent of those observed in AD.Data on the TAS10 line are presented at five time points: 2, 6, 12, 18 and 24 months in a longitudinal study. The TAS10 line is characterised by the following changes: i) significant age-related increases in the levels of total and individual species (1-40, 1-42) of beta-amyloid in the brains of transgenics compared with non-transgenic littermates; ii) transgenic mice showed pronounced spatial learning deficits in the Morris water maze at 6 months and working memory deficits by 12 months; iii) amyloid plaque and associated pathologies were observed by the 12-month time point and the burden increased substantially, particularly in the cortex, by 18 months; iv) electron microscopy of the hippocampus of transgenic mice showed evidence of abnormal ultrastructural features such as dystrophic neurites and lipid deposits that developed from 6 months and increased in number and severity with age. Morphometric studies demonstrate that the synapse to neuron ratio is higher in transgenics than in control mice at 12 months, but this ratio decreases as they age and synapse size increases. Thus, this mouse model exhibits a close correlation of amyloid burden with behavioural deficits and ultrastructural abnormalities and so represents an ideal system to study the mechanisms underlying the impact of amyloid pathology on CNS function.     

Role of water-soluble amyloid-beta in the pathogenesis of Alzheimer's disease

Water-soluble amyloid-beta (wsAbeta) is present in cerebral cortex of subjects at risk of Alzheimer's disease (AD) as well as in normal elderly subjects as a mixture of three major amyloid-beta (Abeta) species: 1-42, py3-42 and py11-42. The three wsAbeta species are nondetectable in brains of young people, free of immunohistochemically detectable amyloid plaques. In the brains of Down's syndrome and APP-mutant transgenic mice, wsAbeta appears long time before amyloid deposition, indicating that it represent the first form of Abeta aggregation and accumulation. In normal brain, wsAbeta is bound to apolipoprotein E that favours its degradation by proteases. The composition of wsAbeta, in terms of the ratio between the full-length 1-42 and the py3-42 peptides, correlates with the severity of clinical and pathological phenotype in familial early onset AD. Water-soluble Abeta is the native counterpart of the Abeta small aggregates (soluble oligomers) that show in vitro an early and high neuronal toxicity.     

Comorbid Rat Model of Ischemia and β‐Amyloid Toxicity: Striatal and Cortical Degeneration

Levels of cerebral amyloid, presumably β‐amyloid (Abeta), toxicity and the incidence of cortical and subcortical ischemia increases with age. However, little is known about the severe pathological condition and dementia that occur as a result of the comorbid occurrence of this vascular risk factor and Abeta toxicity. Clinical studies have indicated that small ischemic lesions in the striatum are particularly important in generating dementia in combination with minor amyloid lesions. These cognitive deficits are highly likely to be caused by changes in the cortex. In this study, we examined the viability and morphological changes in microglial and neuronal cells, gap junction proteins (connexin43) and neuritic/axonal retraction (Fer Kinase) in the striatum and cerebral cortex using a comorbid rat model of striatal injections of endothelin‐1 (ET1) and Abeta toxicity. The results demonstrated ventricular enlargement, striatal atrophy, substantial increases in β‐amyloid, ramified microglia and increases in neuritic retraction in the combined models of stroke and Abeta toxicity. Changes in connexin43 occurred equally in both groups of Abeta‐treated rats, with and without focal ischemia. Although previous behavioral tests demonstrated impairment in memory and learning, the visual discrimination radial maze task did not show significant difference, suggesting the cognitive impairment in these models is not related to damage to the dorsolateral striatum. These results suggest an insight into the relationship between cortical/striatal atrophy, pathology and functional impairment.     

Neuronal or glial expression of human apolipoprotein e4 affects parenchymal and vascular amyloid pathology differentially in different brain regions of double- and triple-transgenic mice

Apolipoprotein E4 (ApoE4) is associated with Alzheimer's disease by unknown mechanisms. We generated six transgenic mice strains expressing human ApoE4 in combination with mutant amyloid precursor protein (APP) and mutant presenilin-1 (PS1) in single-, double-, or triple-transgenic combinations. Diffuse, but not dense, amyloid plaque-load in subiculum and cortex was increased by neuronal but not glial ApoE4 in old (15 months) double-transgenic mice, whereas both diffuse and dense plaques formed in thalamus in both genotypes. Neuronal and glial ApoE4 promoted cerebral amyloid angiopathy as extensively as mutant PS1 but with pronounced regional differences: cortical angiopathy was induced by neuronal ApoE4 while thalamic angiopathy was again independent of ApoE4 source. Angiopathy correlated more strongly with soluble Abeta40 and Abeta42 levels in cortex than in thalamus throughout the six genotypes. Neither neuronal nor glial ApoE4 affected APP proteolytic processing, as opposed to mutant PS1. Neuronal ApoE4 increased soluble amyloid levels more than glial ApoE4, but the Abeta42/40 ratios were similar, although significantly higher than in single APP transgenic mice. We conclude that although the cellular origin of ApoE4 differentially affects regional amyloid pathology, ApoE4 acts on the disposition of amyloid peptides downstream from their excision from APP but without induction of tauopathy.     

Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease

Amyloid plaques appear early during Alzheimer's disease (AD), and their development is intimately linked to activated astrocytes and microglia. Astrocytes are capable of accumulating substantial amounts of neuron-derived, amyloid beta(1-42) (Abeta42)-positive material and other neuron-specific proteins as a consequence of their debris-clearing role in response to local neurodegeneration. Immunohistochemical analyses have suggested that astrocytes overburdened with these internalized materials can eventually undergo lysis, and radial dispersal of their cytoplasmic contents, including Abeta42, can lead to the deposition of a persistent residue in the form of small, GFAP-rich, astrocytic amyloid plaques, first appearing in the molecular layer of the cerebral cortex. Microglia, most of which appear to be derived from blood monocytes and recruited from local blood vessels, rapidly migrate into and congregate within neuritic and dense-core plaques, but not diffuse plaques. Instead of internalizing and removing Abeta from plaques, microglia appear to contribute to their morphological and chemical evolution by facilitating the conversion of existing soluble and oligomeric Abeta within plaques to the fibrillar form. Abeta fibrillogenesis may occur largely within tiny, tube-like invaginations in the surface plasma membrane of microglia. These results highlight the therapeutic potential of blocking the initial intracellular accumulation of Abeta42 in neurons and astrocytes and inhibiting microglia-mediated assembly of fibrillar Abeta, which is particularly resistant to degradation in Alzheimer brain.     

Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function

The amyloid-beta (Abeta) protein exists in the aging mammalian brain in diverse assembly states, including amyloid plaques and soluble Abeta oligomers. Both forms of Abeta have been shown to impair neuronal function, but their precise roles in Alzheimer's disease (AD) -associated memory loss remain unclear. Both types of Abeta are usually present at the same time in the brain, which has made it difficult to evaluate the effects of plaques and oligomers individually on memory function. Recently, a particular oligomeric Abeta assembly, Abeta 56, was found to impair memory function in the absence of amyloid plaques. Until now it has not been possible to determine the effects of plaques, in the absence of Abeta oligomers, on memory function. We have identified Tg2576 mice with plaques but markedly reduced levels of Abeta oligomers, which enabled us to study the effects of plaques alone on memory function. We found that animals with amyloid plaques have normal memory function throughout an episode of reduced Abeta oligomers, which occurs during a period of accelerated amyloid plaque formation. These observations support the importance of Abeta oligomers in memory loss and indicate that, at least initially, amyloid plaques do not impair memory.