Dataset Information

Apolipoprotein E4 and beta amyloid in senile plaques and cerebral blood vessels of aged rhesus monkeys.

ABSTRACT: Recent studies of late onset familial and sporadic Alzheimer's disease (AD) show a genetic disequilibrium between inheritance of the epsilon 4 allele of the apolipoprotein E (ApoE) gene and development of AD. beta-Amyloid (A beta)-positive senile plaques and blood vessels in AD are immunoreactive for ApoE, suggesting that ApoE plays a role in amyloid deposition. We examined the brains of nine rhesus monkeys (Macaca mulatta) to determine the immunohistochemical distribution of ApoE and to investigate the association of ApoE with A beta in this species. Antibodies to ApoE and A beta labeled senile plaques and vessels in the brains of aged monkeys, indicating cross-species homogeneity of the association of these two proteins. Polymerase chain reaction/restriction enzyme analysis of the ApoE epsilon 3/epsilon 4 allelic site (residue 112) in the rhesus monkey revealed that the rhesus has an arginine at this site like the human epsilon 4 allele, the cynomolgus monkey, baboon, cow, pig, mouse, and rat but unlike the human epsilon 3 allele and the rabbit. These results emphasize the value of aged nonhuman primates as animal models for A beta deposition and ApoE4-A beta interactions in AD and aging.

SUBMITTER: Poduri A

PROVIDER: S-EPMC1887468 | biostudies-other | 1994 Jun

REPOSITORIES: biostudies-other

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Apolipoprotein E4 and beta amyloid in senile plaques and cerebral blood vessels of aged rhesus monkeys.

Poduri A A Gearing M M Rebeck G W GW Mirra S S SS Tigges J J Hyman B T BT

The American journal of pathology 19940601 6

Recent studies of late onset familial and sporadic Alzheimer's disease (AD) show a genetic disequilibrium between inheritance of the epsilon 4 allele of the apolipoprotein E (ApoE) gene and development of AD. beta-Amyloid (A beta)-positive senile plaques and blood vessels in AD are immunoreactive for ApoE, suggesting that ApoE plays a role in amyloid deposition. We examined the brains of nine rhesus monkeys (Macaca mulatta) to determine the immunohistochemical distribution of ApoE and to investi ...[more]

PMID: 8203459

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Project description:Accumulating data suggest that cerebrovascular disease contributes to Alzheimer's disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of β-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimer's disease pathology in the ageing brain and increases the risk of Alzheimer's disease dementia. In the present study, we examined whether cerebral amyloid angiopathy influences tau deposition and cognitive decline independently or synergistically with parenchymal β-amyloid burden. Secondly, we examined whether tau burden mediates the association between cerebral amyloid angiopathy and cognitive decline. We included data from autopsied subjects recruited from one of three longitudinal clinical-pathological cohort studies: the Rush Memory and Aging Project, the Religious Orders Study and the Minority Aging Research Study. Participants completed annual clinical and cognitive evaluations and underwent brain autopsy. Cerebral amyloid angiopathy pathology was rated as none, mild, moderate or severe. Bielschowsky silver stain was used to visualize neuritic β-amyloid plaques and neurofibrillary tangles. We used linear regression and linear mixed models to test independent versus interactive associations of cerebral amyloid angiopathy and neuritic plaque burden with tau burden and longitudinal cognitive decline, respectively. We used causal mediation models to examine whether tau mediates the association between cerebral amyloid angiopathy and cognitive decline. The study sample included 1722 autopsied subjects (age at baseline = 80.2 ± 7.1 years; age at death = 89.5 ± 6.7 years; 68% females). Cerebral amyloid angiopathy interacted with neuritic plaques to accelerate tau burden and cognitive decline. Specifically, those with more severe cerebral amyloid angiopathy pathology and higher levels of neuritic plaque burden had greater tau burden and faster cognitive decline. We also found that tau mediated the association between cerebral amyloid angiopathy and cognitive decline among participants with higher neuritic plaque burden. In summary, more severe levels of cerebral amyloid angiopathy and higher parenchymal β-amyloid burden interacted to promote cognitive decline indirectly via tau deposition. These results highlight the dynamic interplay between cerebral amyloid angiopathy and Alzheimer's disease pathology in accelerating progression toward dementia. These findings have implications for Alzheimer's disease clinical trials and therapeutic development.

Project description:Aquaporin-4 (AQP4) is located mainly in the astrocytic end-feet around cerebral blood vessels and regulates ion and water homeostasis in the brain. While deletion of AQP4 is shown to reduce amyloid-β (Aβ) clearance and exacerbate Aβ peptide accumulation in plaques and vessels of Alzheimer's disease mouse models, the mechanism and clearing pathways involved are debated. Here, we investigated how inhibiting the function of AQP4 in healthy male C57BL/6 J mice impacts clearance of Aβ40, the more soluble Aβ isoform. Using two-photon in vivo imaging and visualizing vessels with Sulfurodamine 101 (SR101), we first showed that Aβ40 injected as a ≤ 0.5-μl volume in the cerebral cortex diffused rapidly in parenchyma and accumulated around blood vessels. In animals treated with the AQP4 inhibitor TGN-020, the perivascular Aβ40 accumulation was significantly (P < 0.001) intensified by involving four times more vessels, thus suggesting a generalized clearance defect associated with vessels. Increasing the injecting volume to ≥ 0.5 ≤ 1 μl decreased the difference of Aβ40-positive vessels observed in non-treated and AQP4 inhibitor-treated animals, although the difference was still significant (P = 0.001), suggesting that larger injection volumes could overwhelm intramural vascular clearance mechanisms. While both small and large vessels accumulated Aβ40, for the ≤ 0.5-μl volume group, the average diameter of the Aβ40-positive vessels tended to be larger in control animals compared with TGN-020-treated animals, although the difference was non-significant (P = 0.066). Using histopathology and ultrastructural microscopy, no vascular structural change was observed after a single massive dose of TGN-020. These data suggest that AQP4 deficiency is directly involved in impaired Aβ brain clearance via the peri-/para-vascular routes, and AQP4-mediated vascular clearance might counteract blood-brain barrier abnormalities and age-related vascular amyloidopathy.

Dataset Information

Apolipoprotein E4 and beta amyloid in senile plaques and cerebral blood vessels of aged rhesus monkeys.

Publications

Apolipoprotein E4 and beta amyloid in senile plaques and cerebral blood vessels of aged rhesus monkeys.

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