Absence of synaptophysin near cortical neurons containing oligomer Abeta in Alzheimer's disease brain

Soluble amyloid beta protein (Abeta) oligomers have been considered recently to be responsible for the cognitive dysfunction that sets in prior to senile plaque formation in the Alzheimer's disease (AD) brain. By using the newly prepared antibody against oligomer Abeta, rather than fibrillar or monomer Abeta, we observed that oligomer Abeta in AD brains was localized as clusters ofdot-likeimmunostains in the neurons in a manner different from that in senile plaques. The relationship of oligomer Abeta with synaptophysin, a synaptic molecular marker, was examined because oligomer Abeta is widely believed to be related to synaptic failure. We observed that immunostainings for synaptophysin were absent near neurons bearing clusters of oligomer Abeta. The present study provides morphological evidence to support the idea that accumulated oligomer Abeta, but not fibrillar Abeta, is closely associated with synaptic failure, which is the major cause of cognitive dysfunction.     

Phases of A beta-deposition in the human brain and its relevance for the development of AD

BACKGROUND: The deposition of the amyloid beta protein (Abeta) is a histopathologic hallmark of AD. The regions of the medial temporal lobe (MTL) are hierarchically involved in Abeta-deposition. OBJECTIVE: To clarify whether there is a hierarchical involvement of the regions of the entire brain as well and whether there are differences in the expansion of Abeta-pathology between clinically proven AD cases and nondemented cases with AD-related pathology, the authors investigated 47 brains from demented and nondemented patients with AD-related pathology covering all phases of beta-amyloidosis in the MTL (AbetaMTL phases) and four control brains without any AD-related pathology. METHODS: Abeta deposits were detected by the use of the Campbell-Switzer silver technique and by immunohistochemistry in sections covering all brain regions and brainstem nuclei. It was analyzed how often distinct regions exhibited Abeta deposits. RESULTS: In the first of five phases in the evolution of beta-amyloidosis Abeta deposits are found exclusively in the neocortex. The second phase is characterized by the additional involvement of allocortical brain regions. In phase 3, diencephalic nuclei, the striatum, and the cholinergic nuclei of the basal forebrain exhibit Abeta deposits as well. Several brainstem nuclei become additionally involved in phase 4. Phase 5, finally, is characterized by cerebellar Abeta-deposition. The 17 clinically proven AD cases exhibit Abeta-phases 3, 4, or 5. The nine nondemented cases with AD-related Abeta pathology show Abeta-phases 1, 2, or 3. CONCLUSIONS: Abeta-deposition in the entire brain follows a distinct sequence in which the regions are hierarchically involved. Abeta-deposition, thereby, expands anterogradely into regions that receive neuronal projections from regions already exhibiting Abeta. There are also indications that clinically proven AD cases with full-blown beta-amyloidosis may be preceded in early stages by nondemented cases exhibiting AD-related Abeta pathology.     

Amyloid-beta aggregation

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of AD is the accumulation of plaques in the brain of AD patients. The plaques predominantly consist of aggregates of amyloid-beta (Abeta), a peptide of 39-42 amino acids generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein. There is a growing body of evidence that Abeta aggregates are ordered oligomers and the cause rather than a product of AD. The analysis of the assembly pathway of Abeta in vitro and biochemical characterization of Abeta deposits isolated from AD brains indicate that Abeta oligomerization occurs via distinct intermediates, including oligomers of 3-50 Abeta monomers, annular oligomers, protofibrils, fibrils and plaques. Of these, the most toxic species appear to be small Abeta oligomers. This article reviews the current knowledge of the mechanism of Abeta assembly in vivo and in vitro, as well as the influence of inherited amino acid replacements in Abeta and experimental conditions on Abeta aggregation. Challenges regarding the reproducible handling of the Abeta peptide for in vitro assembly studies are discussed.     

Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism

Receptor-mediated interactions with amyloid beta-peptide (Abeta) could be important in the evolution of the inflammatory processes and cellular dysfunction that are prominent in Alzheimer's disease (AD) pathology. One candidate receptor is the receptor for advanced glycation endproducts (RAGE), which can bind Abeta and transduce signals leading to cellular activation. Data are presented showing a potential mechanism for Abeta activation of microglia that could be mediated by RAGE and macrophage colony-stimulating factor (M-CSF). Using brain tissue from AD and nondemented (ND) individuals, RAGE expression was shown to be present on microglia and neurons of the hippocampus, entorhinal cortex, and superior frontal gyrus. The presence of increased numbers of RAGE-immunoreactive microglia in AD led us to further analyze RAGE-related properties of these cells cultured from AD and ND brains. Direct addition of Abeta(1-42) to the microglia increased their expression of M-CSF. This effect was significantly greater in microglia derived from AD brains compared to those from ND brains. Increased M-CSF secretion was also demonstrated using a cell culture model of plaques whereby microglia were cultured in wells containing focal deposits of immobilized Abeta(1-42). In each case, the Abeta stimulation of M-CSF secretion was significantly blocked by treatment of cultures with anti-RAGE F(ab')2. Treatment of microglia with anti-RAGE F(ab')2 also inhibited the chemotactic response of microglia toward Abeta(1-42). Finally, incubation of microglia with M-CSF and Abeta increased expression of RAGE mRNA. These microglia also expressed M-CSF receptor mRNA. These data suggest a positive feedback loop in which Abeta-RAGE-mediated microglial activation enhances expression of M-CSF and RAGE, possibly initiating an ascending spiral of cellular activation.     

The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging.

The abundance and solubility of Abeta peptides are critical determinants of amyloidosis in Alzheimer's disease (AD). Hence, we compared levels of total soluble, insoluble, and total Abeta1-40 and Abeta1-42 in AD brains with those in age-matched normal and pathologic aging brains using a sandwich enzyme-linked immunosorbent assay (ELISA). Since the measurement of Abeta1-40 and Abeta1-42 depends critically on the specificity of the monoclonal antibodies used in the sandwich ELISA, we first demonstrated that each assay is specific for Abeta1-40 or Abeta1-42 and the levels of these peptides are not affected by the amyloid precursor protein in the brain extracts. Thus, this sandwich ELISA enabled us to show that the average levels of total cortical soluble and insoluble Abeta1-40 and Abeta1-42 were highest in AD, lowest in normal aging, and intermediate in pathologic aging. Remarkably, the average levels of insoluble Abeta1-40 were increased 20-fold while the average levels of insoluble Abeta1-42 were increased only 2-fold in the AD brains compared to pathologic aging brains. Further, the soluble pools of Abeta1-40 and Abeta1-42 were the largest fractions of total Abeta in the normal brain (i.e., 50 and 23%, respectively), but they were the smallest in the AD brain (i.e., 2.7 and 0.7%, respectively) and intermediate (i.e., 8 and 0.8%, respectively) in pathologic aging brains. Thus, our data suggest that pathologic aging is a transition state between normal aging and AD. More importantly, our findings imply that a progressive shift of brain Abeta1-40 and Abeta1-42 from soluble to insoluble pools and a profound increase in the levels of insoluble Abeta1-40 plays mechanistic roles in the onset and/or progression of AD.     

The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer's disease-related pathology

Argyrophilic grain disease (AGD) constitutes a neurodegenerative disorder that occurs in the brains of the elderly and affects 5% of all patients with dementia. Tau protein-containing lesions known as argyrophilic grains and located predominantly in limbic regions of the brain characterize this disease. Dementia is encountered in only a subset of cases that display the morphological pattern of AGD. The aim of this study is to determine the role of concurrent Alzheimer's disease (AD)-related pathology for the development of dementia in AGD patients. A total of 204 post-mortem brains from 30 demented and 49 nondemented AGD patients, 39 AD patients, and from 86 nondemented controls without AGD were staged for AD-related neurofibrillary tangles (NFTs) as well as amyloid beta-protein (Abeta) deposition. To identify differences in AD-related pathology between demented and nondemented AGD cases, and to differentiate the pattern of AD-related changes in demented and nondemented AGD cases from that seen in AD and nondemented controls, we statistically compared the stages of Abeta and NFT distribution among these groups. Using a logistic regression model, we showed that AGD has a significant effect on the development of dementia beyond that attributable to AD-related pathology (P < 0.005). Demented AGD cases showed lower stages of AD-related pathology than did pure AD cases but higher stages than nondemented AGD patients. AGD associated dementia was seen in the presence of NFT (Braak)-stages II-IV and Abeta-phases 2-3, whereas those stages were not associated with dementia in the absence of AGD. In conclusion, AGD is a clinically relevant neurodegenerative entity that significantly contributes to the development of dementia by lowering the threshold for cognitive deficits in the presence of moderate amounts of AD-related pathology.     

Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia

Clinicopathological observations suggest there is considerable overlap between vascular dementia (VaD) and Alzheimer's disease (AD). We used immunochemical methods to compare quantities of amyloid-beta (Abeta) peptides in post mortem brain samples from VaD, AD subjects and nondemented ageing controls. Total Abeta peptides extracted from temporal and frontal cortices were quantified using a previously characterized sensitive homogenous time-resolved fluorescence (HTRF) assay. The HTRF assays and immunocapture mass spectrometric analyses revealed that the Abeta(42) species were by far the predominant form of extractable peptide compared with Abeta(40) peptide in VaD brains. The strong signal intensity for the peak representing Abeta(4-42) peptide confirmed that these N-terminally truncated species are relatively abundant. Absolute quantification by HTRF assay showed that the mean amount of total Abeta(42) recovered from VaD samples was approximately 50% of that in AD, and twice that in the age-matched controls. Linear correlation analysis further revealed an increased accumulation with age of both Abeta peptides in brains of VaD subjects and controls. Interestingly, VaD patients surviving beyond 80 years of age exhibited comparable Abeta(42) concentrations with those in AD in the temporal cortex. Our findings suggest that brain Abeta accumulates increasingly with age in VaD subjects more so than in elderly without cerebrovascular disease and support the notion that they acquire Alzheimer-like pathology in older age.     

Oxidation of Abeta and plaque biogenesis in Alzheimer's disease and Down syndrome

The processes involved with beta-amyloid (Abeta) degradation and clearance in human brain are not well understood. We hypothesized that the distribution of oxidatively modified Abeta, as determined by an affinity-purified antibody in the entorhinal and frontal cortices of Alzheimer's disease (AD), Down syndrome (DS), nondemented elderly control cases, and canine brain, would provide insight into the mechanisms of Abeta accumulation. Based upon plaque counts, oxidized Abeta was present within 46-48% of diffuse and primitive plaques and 98% of cored plaques. Dense punctate deposits of oxidized Abeta were distributed throughout the neuropil in AD and DS brains but were also present within controls with mild neuropathology and isolated cognitive impairments. Confocal studies indicate that punctate oxidized Abeta deposits were within activated microglia. Oxidatively modified Abeta may reflect the efforts of microglial cells to take up and degrade Abeta. Oxidative modification of Abeta may be an early event in Abeta pathogenesis and may be important for plaque biogenesis.     

Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo

Accumulation of the beta-amyloid peptide (Abeta) in the brain is a major pathological hallmark of Alzheimer's disease (AD), leading to synaptic dysfunction, neuronal death, and memory impairment. The levels of neprilysin, a major Abeta-degrading enzyme, are decreased in AD brains and during aging. Because neprilysin cleaves Abeta in vivo, its down-regulation may contribute to the pathophysiology of AD. The aim of this study was to assess the consequences of neprilysin deficiency on accumulation of murine Abeta in brains and associated pathologies in vivo by investigating neprilysin-deficient mice on biochemical, morphological, and behavioral levels. Aged neprilysin-deficient mice expressed physiological amyloid precursor protein (APP) levels and exhibited elevated brain Abeta concentrations and amyloid-like deposits in addition to signs of neuronal degeneration in their brains. Behaviorally, neprilysin-deficient mice acquired a significantly weaker conditioned taste aversion that extinguished faster than the aversion of age-matched controls. Our data establish that, under physiological APP expression levels, neprilysin deficiency is associated with increased Abeta accumulation in the brain and leads to deposition of amyloid-like structures in vivo as well as with signs of AD-like pathology and with behavioral deficits.     

Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1

Transgenic mouse models of Alzheimer's disease (AD) exhibit amyloid-beta (Abeta) accumulation and related cognitive impairments. Although deficits in hippocampus-dependent place learning have been well characterized in Alzheimer's transgenic mice, little is known about temporal memory function in these AD models. Here, we applied trace fear conditioning to two different Alzheimer's mouse models and investigated the relationship between pathogenic Abeta and temporal memory deficits. This behavioral test requires hippocampus-dependent temporal memory processing as the conditioned and unconditioned stimuli are separated by a trace interval of 30 s. We found that both amyloid precursor protein (APP) transgenic (Tg2576) and APP/presenilin (PS)1 transgenic (Tg6799) mice were impaired in memorizing this association across the time gap. Both transgenic groups performed as well as wild-type control mice in delay fear conditioning when the trace interval was removed, indicating that the trace conditioning deficits are hippocampus-specific. Importantly, Tg6799 mice engineered to lack the major Alzheimer's beta-secretase (beta-site APP-cleaving enzyme 1: BACE1) showed behavioral rescue from temporal memory deficits. Elevated levels of soluble Abeta oligomers found in Tg6799+ mouse brains returned to wild-type control levels without changes in APP/PS1 transgene expression in BACE1-/- * Tg6799+ bigenic mouse brains, suggesting Abeta oligomers as potential mediators of memory loss. Thus, trace fear conditioning is a useful assay to test the mechanisms and therapeutic interventions for Abeta-dependent deficits in temporal associative memory. Our gene-based approach suggests that lowering soluble Abeta oligomers by inhibiting BACE1 may be beneficial for alleviating cognitive disorders in AD.     

Reduced levels of Abeta 40 and Abeta 42 in brains of smoking controls and Alzheimer's patients

The effects of nicotine on levels of Abeta 40 and Abeta 42 and nicotinic receptor binding sites were studied in brains from nonsmoking and smoking patients with Alzheimer's disease (AD) and aged-matched controls. The levels of soluble and insoluble Abeta 40 and Abeta 42 in frontal cortex and Abeta 40 in temporal cortex and hippocampus were significantly decreased in smoking AD patients compared to nonsmokers with AD. In smoking controls the levels of soluble and insoluble Abeta 40 and Abeta 42 in the frontal and temporal cortex were significantly lower than in nonsmoking controls. The binding of [(3)H]cytisine in temporal cortex was significantly increased in smokers with AD compared to nonsmokers with AD. In smoking controls [(3)H]cytisine and [(3)H]epibatidine binding were significantly increased from 1.5- to 2-fold compared to nonsmoking controls whereas binding sites for [(125)I]alpha-bungarotoxin was less up-regulated. These results indicate that selective nicotinic receptor agonists may be a novel protective therapy in AD by reducing Abeta levels as well as the loss of nicotinic receptors in AD brain.     

Altered expression of COX-2 in subdivisions of the hippocampus during aging and in Alzheimer's disease: the Hisayama Study

BACKGROUND: It has been reported that nonsteroidal anti-inflammatory drugs may delay the onset of Alzheimer's disease (AD). Since nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase (COX), COX-2, an inducible form of COX, may be involved in the pathology of AD in association with the arachidonic acid cascade. In addition, it has been suggested that alterations in the balance of polyunsaturated fatty acids are associated with brain dysfunctions such as neurodegerative pathologies of the aging brain. METHOD: To explore COX-2 expression in the hippocampus, we analyzed 45 consecutive autopsy subjects without dementia and 25 AD patients derived from the town of Hisayama, Japan. RESULTS: The neuronal expression of COX-2 in the CA3 subdivision of the hippocampus, subiculum, entorhinal cortex and transentorhinal cortex were consistently observed in both nondemented and AD brains, and COX-2 immunoreactivity correlated with age in nondemented brains. In AD patients, neurons of CA1 exhibited increased COX-2 immunoreactivity which correlated with the severity of AD pathology. This correlation was not apparent in nondemented subjects. CONCLUSION: These results suggest that COX-2 expression may be differentially regulated among subdivisions of the hippocampus and that elevated COX-2 expression in the CA1 of AD brains may be associated with AD pathology and thus cognitive dysfunction.     

Heme binding to Amyloid-beta peptide: mechanistic role in Alzheimer's disease

Genetic, biochemical, and immunological evidences support a mechanistic role for amyloid-beta (Abeta) peptide in the pathophysiology of Alzheimer's disease (AD). Abeta appears to trigger most of the disparate cytopathologies of AD (e.g. loss of iron homeostasis and mitochondrial complex IV), which may initiate synaptic dysfunction, hypometabolism, and memory loss. However, the molecular mechanism that links Abeta to the neurodegeneration of AD is not clear. We have provided evidence for heme's key role in the important cytopathologies of AD, hypothesizing a functional deficiency for heme in the brains of AD patients. The molecular link between beta and heme required to support this hypothesis was demonstrated by our discovery that heme binds with Abeta, forming a complex (Abeta-heme). Heme prevented the aggregation of Abeta by forming Abeta-heme, suggesting Abeta-heme may prevent Abeta aggregation in vivo. The downside, however, is that Abeta-heme is a peroxidase, which if not regulated might indiscriminately oxidize diverse biomolecules. Additionally, excessive production of Abeta in AD brain may bind to and restrict the bioavailability of regulatory heme, creating a condition of heme-deficiency. Regulatory heme regulates heme synthesis, iron homeostasis, specific signaling pathways, and intermediary metabolism. A novel model of Abeta-induced heme-deficiency leading to mitochondrial dysfunction, Abeta-heme peroxidase, and altered metabolic activity is presented. Genetic, nutritional, and toxicological factors that influence heme metabolism will be discussed in relevance to AD.     

Trehalose differentially inhibits aggregation and neurotoxicity of beta-amyloid 40 and 42

A key event in Alzheimer's disease (AD) pathogenesis is the conversion of the peptide beta-amyloid (Abeta) from its soluble monomeric form into various aggregated morphologies in the brain. Preventing aggregation of Abeta is being actively pursued as a primary therapeutic strategy for treating AD. Trehalose, a simple disaccharide, has been shown to be effective in preventing the deactivation of numerous proteins and in protecting cells against stress. Here, we show that trehalose is also effective in inhibiting aggregation of Abeta and reducing its cytotoxicity, although it shows differential effects toward Abeta40 and Abeta42. When co-incubated with Abeta40, trehalose inhibits formation of both fibrillar and oligomeric morphologies as determined by fluorescence staining and atomic force microscopy (AFM). However, when co-incubated with Abeta42, trehalose inhibits formation only of the fibrillar morphology, with significant oligomeric formation still present. When aggregated mixtures were incubated with SH-SY5Y cells, trehalose was shown to reduce the toxicity of Abeta40 mixtures, but not Abeta42. These results provide additional evidence that aggregation of Abeta into soluble oligomeric forms is a pathological step in AD and that Abeta42 in particular is more susceptible to forming these toxic oligomers than Abeta40. These results also suggest that the use of trehalose, a highly soluble, low-priced sugar, as part of a potential therapeutic cocktail to control Abeta peptide aggregation and toxicity warrants further study.     

Pathogenic role of mitochondrial [correction of mitochondral] amyloid-beta peptide

Metabolic dysfunction is one of the early features in Alzheimer's disease (AD) affected brain. Amyloid-beta peptide (Abeta), a major peptide deposited in neuritic plaques, has been considered as an important initiating molecule in the pathogenesis of AD. However, the pathogenic role of Abeta remains to be determined. Here, we review current studies showing that progressive accumulation of Abeta occurs within the mitochondria of both transgenic mice overexpressing mutant Abeta peptide precursor protein and autopsied brains from AD patients. Interaction of Abeta with Abeta-binding alcohol dehydrogenase (ABAD), a short-chain alcohol dehydrogenase in the mitochondrial matrix, leads to mitochondrial dysfunction evidenced by increased reactive oxygen species generation, mitochondrial membrane permeability formation and caspase-3-like activity induction, and decreased activities of the Krebs cycle. These effects can be blocked by intracellular transduction of the ABAD decoy peptide. We hypothesize that Abeta-induced and mitochondria-dependent cytotoxic pathways might play an important role in AD pathogenesis and could be a potential therapeutic target.     

Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?

Amyloid beta (Abeta) is a small self-aggregating peptide produced at low levels by normal brain metabolism. In Alzheimer's disease (AD), self-aggregation of Abeta becomes rampant, manifested most strikingly as the amyloid fibrils of senile plaques. Because fibrils can kill neurons in culture, it has been argued that fibrils initiate the neurodegenerative cascades of AD. An emerging and different view, however, is that fibrils are not the only toxic form of Abeta, and perhaps not the neurotoxin that is most relevant to AD: small oligomers and protofibrils also have potent neurological activity. Immuno-neutralization of soluble Abeta-derived toxins might be the key to optimizing AD vaccines that are now on the horizon.     

Differential effects of oligomeric and fibrillar amyloid-beta 1-42 on astrocyte-mediated inflammation

Activated glia, as a result of chronic inflammation, are associated with amyloid-beta peptide (Abeta) deposits in the brain of Alzheimer's disease (AD) patients. In vitro, glia are activated by Abeta inducing secretion of pro-inflammatory molecules. Recent studies have focused on soluble oligomers (or protofibrils) of Abeta as the toxic species in AD. In the present study, using rat astrocyte cultures, oligomeric Abeta induced initial high levels of IL-1beta decreasing over time and, in contrast, fibrillar Abeta increased IL-1beta levels over time. In addition, oligomeric Abeta, but not fibrillar Abeta, induced high levels of iNOS, NO, and TNF-alpha. Our results suggest that oligomers induced a profound, early inflammatory response, whereas fibrillar Abeta showed less increase of pro-inflammatory molecules, consistent with a more chronic form of inflammation.     

BACE inhibitors as potential therapeutics for Alzheimer's disease

Accumulation of Abeta peptide in the brain results in the formation of amyloid plaques characteristic of Alzheimer's disease (AD) pathology. Abeta soluble oligomers and protofibrils are neurotoxic and these are believed to be a major cause of neurodegeneration in AD. Abeta is derived from a precursor protein by two sequential cleavage steps involving beta- and gamma-secretases, two proteolytic enzymes that represent rational drug targets. beta-secretase was identified as the membrane-anchored aspartyl protease BACE (or BACE1) and found to be elevated in brain cortex of patients with sporadic Alzheimer's disease. In this review, we summarize current approaches towards the development of BACE inhibitors with focus on bioactive compounds and related patents. Recent reports have described drugs that are effective at inhibiting Abeta production in the brain of transgenic mouse models. The beginning of Phase I clinical trials has been approved for one of them and we can expect that in the near future BACE inhibitors will provide novel effective therapeutics to treat AD.     

Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomers

OBJECTIVE: Despite progress in defining a pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, orally bioavailable compounds that prevent its effects on hippocampal synaptic plasticity and cognitive function have not yet emerged. A particularly attractive therapeutic strategy is to selectively neutralize small, soluble Abeta oligomers that have recently been shown to mediate synaptic dysfunction. METHODS: Using electrophysiological, biochemical, and behavioral assays, we studied how scyllo-inositol (AZD-103; molecular weight, 180) neutralizes the acutely toxic effects of Abeta on synaptic function and memory recall. RESULTS: Scyllo-inositol, but not its stereoisomer, chiro-inositol, dose-dependently rescued long-term potentiation in mouse hippocampus from the inhibitory effects of soluble oligomers of cell-derived human Abeta. Cerebroventricular injection into rats of the soluble Abeta oligomers interfered with learned performance on a complex lever-pressing task, but administration of scyllo-inositol via the drinking water fully prevented oligomer-induced errors. INTERPRETATION: A small, orally available natural product penetrates into the brain in vivo to rescue the memory impairment produced by soluble Abeta oligomers through a mechanism that restores hippocampal synaptic plasticity.     

In vivo cerebrovascular actions of amyloid beta-peptides and the protective effect of conjugated estrogens

Vascular dysfunction and inflammatory processes may be early events in the pathology of Alzheimer's disease (AD). Even though amyloid beta-peptides (Abeta) play a prominent role in the initiation and progression of cellular dysfunction in AD, the precise in vivo actions of various Abeta-peptides has not been established. The cerebrovascular actions of the major Abeta-peptides (1-40) and (1-42) in live animals were investigated using an open cranial window technique. We show here that the Abeta-peptides cause vascular lesions, especially in the arterioles. In one set of experiments, leukocytes and platelets were tagged with Rhodamine 6G, soluble Abeta(1-40) infused intravenously for 2 minutes, and the vasculature video recorded for 90 minutes. In a second set of experiments, soluble Abeta(1-40) infusion was followed 30 minutes later by an infusion of soluble Abeta(1-42) and the vasculature recorded for 90 minutes. Fluorescent and transmission electron microscopic examinations demonstrated the following cerebrovascular action of Abeta-peptides: endothelial cell damage, leukocyte adhesion, platelet activation, thrombus formation, impeded blood flow, and smooth muscle cell damage. The vascular disruption observed were similar to those observed in the brains of some AD patients and may represent the initial phase of a vascular inflammatory response associated with cerebral amyloid angiopathy. The combination of Abeta(1-40) and (1-42) produced significantly more vascular disruption than Abeta(1-40) alone. Oral administration of conjugated estrogens in ovariectomized female rats protected them from the deleterious actions of Abeta-peptides. The reported protective effect of estrogen against AD may be mediated in part through prevention of cerebrovascular Abeta toxicity.