Dataset Information

Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy.

ABSTRACT: Neuronal accumulation of oligomeric amyloid-beta (Alphabeta) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce Abeta stress to neurons by immigration into the brain and phagocytosis of Alphabeta. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of Alphabeta by AD and normal subjects' macrophages. Both AD and normal macrophages were inhibited in Alphabeta export across the blood-brain barrier due to adherence of Abeta-engorged macrophages to the endothelial layer. In comparison to normal subjects' macrophages, AD macrophages ingested and cleared less Alphabeta, and underwent apoptosis upon exposure to soluble, protofibrillar, or fibrillar Alphabeta. Confocal microscopy of stained AD brain sections revealed oligomeric Abeta in neurons and apoptotic macrophages, which surrounded and infiltrated congophilic microvessels, and fibrillar Abeta in plaques and microvessel walls. After incubation with AD brain sections, normal subjects' monocytes intruded into neurons and uploaded oligomeric Abeta. In conclusion, in patients with AD, macrophages appear to shuttle Abeta from neurons to vessels where their apoptosis may release fibrillar Abeta, contributing to cerebral amyloid angiopathy.

SUBMITTER: Zaghi J

PROVIDER: S-EPMC5650912 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy.

Zaghi Justin J Goldenson Ben B Inayathullah Mohammed M Lossinsky Albert S AS Masoumi Ava A Avagyan Hripsime H Mahanian Michelle M Bernas Michael M Weinand Martin M Rosenthal Mark J MJ Espinosa-Jeffrey Araceli A de Vellis Jean J Teplow David B DB Fiala Milan M

Acta neuropathologica 20090113 2

Neuronal accumulation of oligomeric amyloid-beta (Alphabeta) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce Abeta stress to neurons by immigration into the brain and phagocytosis of Alphabeta. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of Alphabeta by AD and normal subjects' macrophages. Both AD and normal macrophages were inhibited in Alphabeta export across the b ...[more]

PMID: 19139910

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Project description:Several pieces of evidence suggest that blood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD), exemplified by the frequent occurrence of cerebral amyloid angiopathy (CAA) and the defective clearance of Aβ peptides. However, the specific role of brain microvascular cells in these anomalies remains elusive. In this study, we validated by Western, ELISA and immunofluorescence analyses a procedure to generate microvasculature-enriched fractions from frozen samples of human cerebral cortex. We then investigated Aβ and proteins involved in its clearance or production in microvessel extracts generated from the parietal cortex of 60 volunteers in the Religious Orders Study. Volunteers were categorized as AD (n = 38) or controls (n = 22) based on the ABC scoring method presented in the revised guidelines for the neuropathological diagnosis of AD. Higher ELISA-determined concentrations of vascular Aβ40 and Aβ42 were found in persons with a neuropathological diagnosis of AD, in apoE4 carriers and in participants with advanced parenchymal CAA, compared to respective age-matched controls. Vascular levels of two proteins involved in Aβ clearance, ABCB1 and neprilysin, were lower in persons with AD and positively correlated with cognitive function, while being inversely correlated to vascular Aβ40. In contrast, BACE1, a protein necessary for Aβ production, was increased in individuals with AD and in apoE4 carriers, negatively correlated to cognitive function and positively correlated to Aβ40 in microvessel extracts. The present report indicates that concentrating microvessels from frozen human brain samples facilitates the quantitative biochemical analysis of cerebrovascular dysfunction in CNS disorders. Data generated overall show that microvessels extracted from individuals with parenchymal CAA-AD contained more Aβ and BACE1 and less ABCB1 and neprilysin, evidencing a pattern of dysfunction in brain microvascular cells contributing to CAA and AD pathology and symptoms.

Dataset Information

Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy.

Publications

Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy.

Similar Datasets

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