Cerebral Beta-amyloidosis Research Articles

Comparison of Plasma Lipoprotein Composition and Function in Cerebral Amyloid Angiopathy and Alzheimer's Disease.

Cerebral amyloid angiopathy (CAA) refers to beta-amyloid (Aβ) deposition in brain vessels and is clinically the main cause of lobar intracerebral hemorrhage (ICH). Aβ can also accumulate in brain parenchyma forming neuritic plaques in Alzheimer’s disease (AD). Our study aimed to determine whether the peripheral lipid profile and lipoprotein composition are associated with cerebral beta-amyloidosis pathology and may reflect biological differences in AD and CAA. For this purpose, lipid and apolipoproteins levels were analyzed in plasma from 51 ICH-CAA patients (collected during the chronic phase of the disease), 60 AD patients, and 60 control subjects. Lipoproteins (VLDL, LDL, and HDL) were isolated and their composition and pro/antioxidant ability were determined. We observed that alterations in the lipid profile and lipoprotein composition were remarkable in the ICH-CAA group compared to control subjects, whereas the AD group presented no specific alterations compared with controls. ICH-CAA patients presented an atheroprotective profile, which consisted of lower total and LDL cholesterol levels. Plasma from chronic ICH-CAA patients also showed a redistribution of ApoC-III from HDL to VLDL and a higher ApoE/ApoC-III ratio in HDL. Whether these alterations reflect a protective response or have a causative effect on the pathology requires further investigation.

Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in down syndrome

IntroductionAdults with Down syndrome are genetically predisposed to develop Alzheimer’s disease and accumulate beta-amyloid plaques (Aβ) early in life. While Aβ has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aβ burden. MethodsA total of 161 adults with Down syndrome (mean age = 39.2 (8.50) years) and 40 healthy, non-Down syndrome sibling controls (43.2 (12.6) years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans. PET images were converted to units of standardized uptake value ratios (SUVrs). Aβ burden was calculated using the amyloid load metric (AβL); a measure of global Aβ burden that improves quantification from SUVrs by suppressing the nonspecific binding signal component and computing the specific Aβ signal from all Aβ-carrying voxels from the image. Regional tau was assessed using control-standardized AV-1451 SUVr. Control-standardized SUVrs were compared across Down syndrome groups of Aβ-negative (A-) (AβL < 13.3), subthreshold A+ (13.3 ≤ AβL < 20) and conventionally A+ (AβL ≥ 20) individuals. The subthreshold A + group was identified as having significantly higher Aβ burden compared to the A- group, but not high enough to satisfy a conventional A + classification. ResultsA large-sized association that survived adjustment for chronological age, mental age (assessed using the Peabody Picture Vocabulary Test), and imaging site was observed between AβL and AV-1451 within each Braak region (p < .05). The A + group showed significantly higher AV-1451 retention across all Braak regions compared to the A- and subthreshold A + groups (p < .05). The subthreshold A + group showed significantly higher AV-1451 retention in Braak regions I-III compared to an age-matched sample from the A- group (p < .05). DiscussionThese results show that even the earliest detectable Aβ accumulation in Down syndrome is accompanied by elevated tau in the early Braak stage regions. This early detection of tau can help characterize the tau accumulation phase during preclinical Alzheimer’s disease progression in Down syndrome and suggests that there may be a relatively narrow window after Aβ accumulation begins to prevent the downstream cascade of events that leads to Alzheimer’s disease.

Low-Density Lipoprotein Particle Size Subfractions and Cerebral Amyloidosis.

Cerebral beta-amyloidosis (CA) is a condition in which amyloid-β (Aβ) proteins are deposited in the cerebral cortex and is a predictor of Alzheimer's disease (AD). The Aging Brain Study (ABS) investigated risk factors for CA in persons with diabetes and dyslipidemia. In the ABS, we identified that greater levels of LDL cholesterol and lower levels of HDL cholesterol were associated with increased CA. LDL particles comprise multiple species of varying size, density, and protein composition. For example, within a lipoprotein profile characteristic for persons with obesity and diabetic dyslipidemia, larger LDL particles have a greater ApoE to ApoB ratio, enhancing their binding affinity to LDL receptors. The goal of this study was to identify LDL particles that associate with CA in ABS. LDL particle size fractions were measured by ion mobility in plasma samples of 58 participants (40 women and 18 men). CA was assessed using Pittsburgh Compound B index-Positron Emission Tomography (PiB-PET) imaging. Among the LDL subfractions, greater plasma levels of large LDL particles were significantly associated with greater cerebral amyloidosis and lower hippocampal volumes independent of LDL cholesterol or triglyceride levels. Since Aβ is cleared by the LDL receptor family, such as lipoprotein-like receptor 1 (LRP1), one potential mechanism for our findings is competition between ApoE enriched larger LDL particles and brain-derived Aβ on hepatic Aβ clearance and degradation. We conclude that assessing larger LDL particles in persons with atherogenic dyslipidemia may provide a mechanistic biomarker for the extent of CA.

T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer’s disease-like cerebral amyloidosis

Cerebral beta-amyloidosis, one of the pathological hallmarks of Alzheimer’s disease (AD), elicits a well-characterised, microglia-mediated local innate immune response. In contrast, it is not clear whether cells of the adaptive immune system, in particular T-cells, react to cerebral amyloidosis in AD. Even though parenchymal T-cells have been described in post-mortem brains of AD patients, it is not known whether infiltrating T-cells are specifically recruited to the extracellular deposits of beta-amyloid, and whether they are locally activated into proliferating, effector cells upon interaction with antigen-presenting cells (APCs). To address these issues we have analysed by confocal microscopy and flow-cytometry the localisation and activation status of both T-cells and APCs in transgenic (tg) mice models of AD-like cerebral amyloidosis. Increased numbers of infiltrating T-cells were found in amyloid-burdened brain regions of tg mice, with concomitant up-regulation of endothelial adhesion molecules ICAM-1 and VCAM-1, compared to non-tg littermates. The infiltrating T-cells in tg brains did not co-localise with amyloid plaques, produced less interferon-gamma than those in controls and did not proliferate locally. Bona-fide dendritic cells were virtually absent from the brain parenchyma of both non-tg and tg mice, and APCs from tg brains showed an immature phenotype, with accumulation of MHC-II in intracellular compartments. These results indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local antigen presentation and T-cell activation. The inability of the brain immune surveillance to orchestrate a protective immune response to amyloid-beta peptide might contribute to the accumulation of amyloid in the progression of the disease.

CSF beta-amyloid 42 and t-tau profile in murine models of cerebral beta-amyloidosis

CSF beta-amyloid 42 and t-tau profile in murine models of cerebral beta-amyloidosis

Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis

Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis

Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis.

The intracerebral injection of β-amyloid-containing brain extracts can induce cerebral β-amyloidosis and associated pathologies in susceptible hosts. We found that intraperitoneal inoculation with β-amyloid-rich extracts induced β-amyloidosis in the brains of β-amyloid precursor protein transgenic mice after prolonged incubation times.

P2-067: PIB binding in Alzheimer's disease and nonhuman primate brain

Background: The amyloid cascade hypothesis implicates the Abeta peptide as an upstream effector in Alzheimer’s disease (AD) neurodegeneration. However, the deposition of Abeta in the human brain is not always associated with frank dementia, inasmuch as abundant Abeta lesions are sometimes found in the brains of aged humans without overt cognitive impairment. Furthermore, age-related accumulation of cerebral Abeta is commonly observed in nonhuman primates, yet no nonhuman species has been shown to exhibit the full behavioral or pathological characteristics of AD. Because of their close biological relationship to humans, nonhuman primates are a unique model of nonpathologic Abeta accumulation. We have extensively characterized cerebral Abeta populations in AD, aged chimpanzees, rhesus macaques, and squirrel monkeys. Methods: Using immunohistochemistry, ELISA, immunoprecipitation/ MALDI-TOF MS and in vivo Abeta-seeding assays, we found that Abeta populations are quantitatively and qualitatively similar in AD and nonhuman primate brain. To explain the pathological differences between humans and other primates, we hypothesized that higher-order structural features distinguish toxic Abeta in AD brain from the relatively benign Abeta in nonhuman primates. Recent reports show that Pittsburgh Compound B (PIB), a radioligand used for in vivo PET imaging of amyloid, binds with high affinity and stoichiometry to AD brain but with low stoichiometry to synthetic Abeta and to the Abeta deposits in transgenic mouse brain. We measured the binding of 3H-PIB to cortical homogenates from AD and nonhuman primate cases, all of which had been characterized for total soluble and insoluble Abeta levels. Results: We found that 3H-PIB binds with low stoichiometry to Abeta in nonhuman primate cortical homogenates, even in cases with levels of Abeta equal to those in AD. Conclusions: These data suggest that cerebral beta-amyloid deposits in aged nonhuman primates, which naturally develop cerebral beta-amyloidosis over the course of many years, are structurally distinct from those in humans with AD, and that high-affinity PIB binding may be relatively selective for pathogenic Abeta in the AD brain.

S5-03-03: Induction of cerebral beta-amyloidosis in transgenic mice

We have previously shown (Meyer-Lühmann et al., Science 313: 1781–84, 2006) that intracerebral injections of dilute, amyloid-beta (Abeta)-containing human or APP transgenic mouse brain extract can induce cerebral beta-amyloidosis and associated pathology in APP transgenic mice in a time- and concentration-dependent manner. After injecting extracts from APP/PS1 transgenic mice into APP hosts and vice versa, our results suggest the occurrence of polymorphic Abeta species, reminiscent of prion strains. We use dilute brain extracts as described in Meyer-Lühmann et al., Science 313: 1781–84, 2006. Results from ongoing experiments will be presented. The nature of the seeding agent and of the induced amyloid will be further characterized and peripheral routes of extract applications studied.

The value of incomplete mouse models of Alzheimer’s disease

To study Alzheimer's disease (AD), a variety of mouse models has been generated through the overexpression of the amyloid precursor protein and/or the presenilins harboring one or several mutations found in familial AD. With aging, these mice develop several lesions similar to those of AD, including diffuse and neuritic amyloid deposits, cerebral amyloid angiopathy, dystrophic neurites and synapses, and amyloid-associated neuroinflammation. Other characteristics of AD, such as neurofibrillary tangles and nerve cell loss, are not satisfactorily reproduced in these models. Mouse models that recapitulate only specific aspects of AD pathogenesis are of great advantage when deciphering the complexity of the disease and can contribute substantially to diagnostic and therapeutic innovations. Incomplete mouse models have been key to the development of Abeta42-targeted therapies, as well as to the current understanding of the interrelationship between cerebral beta-amyloidosis and tau neurofibrillary lesions, and are currently being used to develop novel diagnostic agents for in vivo imaging.

Very long term studies of the seeding of β-amyloidosis in primates

Cerebral beta-amyloidosis was found in 16/18 marmosets aged <10 yrs and 8/9 marmosets aged >10 yrs, injected intracerebrally with human or marmoset brain homogenate containing beta-amyloid 1-8 years previously. It was found in only 2/12 marmosets aged <10 yrs and 1/15 marmosets aged >10 yrs, injected with synthetic Abeta-peptides, CSF, or brain tissue which did not contain beta-amyloid. Cerebral beta-amyloidosis was found in 0/11 uninjected marmosets aged <10 yrs and in 5/29 uninjected marmosets aged >10 yrs. The beta-amyloidosis comprised small and large vessel angiopathy and some plaques throughout cortex and was qualitatively similar in injected marmosets and, when present, in uninjected marmosets. Of those injected marmosets which were positive, the amount of beta-amyloidosis was unrelated to age or incubation times but the 3 injected marmosets without beta-amyloidosis had incubation times of <3.5 years. We conclude that beta-amyloid, or associated factors, can initiate or accelerate the process of cerebral amyloidosis in primates.

Circulating Levels of Soluble Receptor for Advanced Glycation End Products in Alzheimer Disease and Vascular Dementia

The receptor for advanced glycation end products (RAGE) is a cell surface receptor that has been implicated in vascular disease and neurodegeneration. Low levels of its secreted isoform, soluble RAGE (sRAGE), have been regarded as a putative risk factor for atherosclerosis. In addition, administration of sRAGE has been shown to reduce development of cerebral beta-amyloidosis in an Alzheimer disease mouse model. To investigate the role of sRAGE as a biological marker for Alzheimer disease and vascular dementia. Cross-sectional study of 152 patients with a clinical diagnosis of Alzheimer disease, 91 with vascular dementia and 161 control subjects. Plasma levels of sRAGE. Levels of sRAGE were significantly reduced in the plasma of patients with Alzheimer disease compared with that for those with either vascular dementia (P<.05) or with controls (P<.001). Patients with Alzheimer disease have reduced levels of sRAGE in plasma compared with patients with vascular dementia and controls. The striking reduction of circulating sRAGE in Alzheimer disease further supports a role for the RAGE axis in this clinical entity and requires further investigation.

Association of Aortic Atherosclerosis with Cerebral β-Amyloidosis and Learning Deficits in a Mouse Model of Alzheimer's Disease

High fat/high cholesterol diets exacerbate beta-amyloidosis in mouse models of Alzheimer's disease (AD). It has been impossible, however, to study the relationship between atherosclerosis and beta-amyloidosis in those models because such mice were on atherosclerosis-resistant genetic backgrounds. Here we report the establishment of AD model mice, B6Tg2576, that are prone to atherosclerosis. B6Tg2576 mice were produced by back-crossing Tg2576 mice, an AD mouse model overexpressing human amyloid beta-protein precursor with the Swedish double mutation, to C57BL/6 mice, a strain susceptible to diet-induced atherosclerosis. An atherogenic diet induced aortic atherosclerosis and exacerbated cerebral beta-amyloidosis in B6Tg2576 mice. Compared with age-matched non-transgenic littermates, B6Tg2576 mice developed significantly more diet-induced aortic atherosclerosis. Unexpectedly, normal diet-fed B6Tg2576 mice also developed fatty streak lesions (early atherosclerosis) in the aorta. The aortic atherosclerotic lesion area positively correlated with cerebral beta-amyloid deposits in B6Tg2576 mice on both atherogenic and normal diets. Furthermore, behavioral assessments demonstrated that B6Tg2576 mice fed an atherogenic diet had more spatial learning impairment than those fed a normal diet. Our results suggest that synergistic mechanisms may be involved in the pathogenesis of atherosclerosis and AD. These findings may have important implications in the prevention and treatment of cardiovascular diseases as well as AD.

Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis.

Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.

Cholinergic Changes in the APP23 Transgenic Mouse Model of Cerebral Amyloidosis

Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.

Elimination of the Class A Scavenger Receptor Does Not Affect Amyloid Plaque Formation or Neurodegeneration in Transgenic Mice Expressing Human Amyloid Protein Precursors

The class A scavenger receptor (SR) is expressed on reactive microglia surrounding cerebral amyloid plaques in Alzheimer's disease (AD). Interactions between the SR and amyloid beta peptides (Abeta) in microglial cultures elicit phagocytosis of Abeta aggregates and release of neurotoxins. To assess the role of the SR in amyloid clearance and Abeta-associated neurodegeneration in vivo, we used the platelet-derived growth factor promoter to express human amyloid protein precursors (hAPPs) in neurons of transgenic mice. With increasing age, hAPP mice develop AD-like amyloid plaques. We bred heterozygous hAPP (hAPP(+/-)) mice that were wild type for SR (SR(+/+)) with SR knockout (SR(-/-)) mice. Crosses among the resulting hAPP(+/-)SR(+/-) offspring yielded hAPP(+/-) and hAPP(-/-) littermates that were SR(+/+) or SR(-/-). These second-generation mice were analyzed at 6 and 12 months of age for extent of cerebral amyloid deposition and loss of synaptophysin-immunoreactive presynaptic terminals. hAPP(-/-)SR(-/-) mice showed no lack of SR expression, plaque formation, or synaptic degeneration, indicating that lack of SR expression does not result in significant accumulation of endogenous amyloidogenic or neurotoxic factors. In hAPP(+/-) mice, ablation of SR expression did not alter number, extent, distribution, or age-dependent accumulation of plaques; nor did it affect synaptic degeneration. Our results do not support a critical pathogenic role for microglial SR expression in neurodegenerative alterations associated with cerebral beta amyloidosis.

Apolipoprotein E4 promotes incipient Alzheimer pathology in the elderly.

To evaluate the influence of the apolipoprotein E (ApoE) epsilon4 allele on the age at which Alzheimer-like lesions appear in the brain, we analyzed the degree of cerebral beta-amyloidosis and neurofibrillary tangle formation in the hippocampal formation and adjacent cortical areas 28, 27, and 36 of persons who had died between the ages of 50 and 93 years and who had shown no signs of clinical dementia. The occurrence of the three common polymorphisms of the ApoE gene in this sample of 147 routine autopsy cases from eastern Germany was comparable to previously reported values in European and North American populations: ApoEepsilon2/2, 0.7%; ApoEepsilon2/3, 14.3%; ApoEepsilon2/4, 4.1%; ApoEepsilon3/3, 56.5%; ApoEepsilon3/4, 22.4%; and ApoEepsilon4/4, 2.0%. Nondemented persons carrying the ApoEepsilon4 allele were significantly more likely to have senile plaques, diffuse amyloid deposits, cerebrovascular amyloid, and neurofibrillary tangles than were those lacking E4. Comparing the two largest ApoE subgroups, ApoEepsilon3/3 and ApoEepsilon3/4, the relative increase in the occurrence of beta-amyloid in the epsilon3/4 group was evident by the mid-60s, with the relative increase in neurofibrillary tangles in this group emerging slightly earlier. The ApoEepsilon2 allele appears to delay the appearance of the lesions somewhat. We conclude that ApoEepsilon4 promotes the early appearance of beta-amyloid and neurofibrillary tangles in the elderly and that the increased frequency of these lesions is related to the higher risk of Alzheimer disease in persons bearing the ApoEepsilon4 allele.

The age of biosenescence and the incidence of cerebral beta-amyloidosis in aged captive rhesus monkeys.

Autopsy surveillance of 186 rhesus monkeys aged 20 to 36 years revealed that development of major geriatric diseases such as emphysema, coronary sclerosis, and cancer increased rapidly after the age of 25 years, and nearly 70% of the monkeys in each cohort group died by 30 years. According to our 12-year longitudinal survey, the age of biosenescence in captive rhesus monkeys begins around 25 years and the maximum longevity is 36 years. The incidence of cerebral beta-amyloidosis associated with plaque formation and cerebral angiopathy was observed in 51 brains of rhesus monkeys aged 25 to 36 years. Lesions were found in 31 of 51 aged brains (60%) and 6 monkeys over 34 years of age were all severely affected. Despite the size of the plaque, nearly all of them showed immunopositive beta-amyloid. Cerebral angiopathy coexisted in 10 of 31 plaque-positive brains. The basal prefrontal gyrus was the most common site and contained the highest density of plaques, followed by the amygdala region. The amyloid in the liver, spleen, adrenal and pancreatic islets in visceral amyloidosis showed no positivity to the beta-amyloid demonstrated in the brain. As in aged human brains, the incidence of age-dependent cerebral beta-amyloidosis in captive rhesus monkeys showed great individual variation.