Dataset Information

Amyloid ? toxic conformer has dynamic localization in the human inferior parietal cortex in absence of amyloid plaques.

ABSTRACT: Amyloid ? (A?) plays a critical role in the pathogenesis of Alzheimer's disease. Nevertheless, its distribution and clearance before A? plaque formation needs to be elucidated. Using an optimized immunofluorescent staining method, we examined the distribution of A? in the post-mortem parietal cortex of 35 subjects, 30 to 65 years of age, APOE ?3/?3, without AD lesions. We used 11A1, an antibody against an A? conformer which forms neurotoxic oligomers. 11A1 immunoreactivity (IR) was present in cortical neurons, pericapillary spaces, astrocytes and the extracellular compartment at 30 years of age. The percentage of neurons with 11A1 IR did not change with age, but the number and percentage of astrocytes with 11A1 IR gradually increased. Notably, the percentage of pericapillary spaces labeled with 11A1 IR declined significantly in the 5th decade of the life, at the same time that 11A1 IR increased in the extracellular space. Our findings indicate that the A? toxic conformer is normally present in various cell types and brain parenchyma, and appears to be constitutively produced, degraded, and cleared from the inferior parietal cortex. The decrease in pericapillary A? and the concomitant increase of extracellular A? may reflect an age-associated impairment in A? clearance from the brain.

SUBMITTER: Kageyama Y

PROVIDER: S-EPMC6237870 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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Amyloid β toxic conformer has dynamic localization in the human inferior parietal cortex in absence of amyloid plaques.

Kageyama Yusuke Y Saito Atsushi A Pletnikova Olga O Rudow Gay L GL Irie Yumi Y An Yang Y Murakami Kazuma K Irie Kazuhiro K Resnick Susan M SM Fowler David R DR Martin Lee J LJ Troncoso Juan C JC

Scientific reports 20181115 1

Amyloid β (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease. Nevertheless, its distribution and clearance before Aβ plaque formation needs to be elucidated. Using an optimized immunofluorescent staining method, we examined the distribution of Aβ in the post-mortem parietal cortex of 35 subjects, 30 to 65 years of age, APOE ε3/ε3, without AD lesions. We used 11A1, an antibody against an Aβ conformer which forms neurotoxic oligomers. 11A1 immunoreactivity (IR) was present in co ...[more]

PMID: 30442978

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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

Amyloid ? toxic conformer has dynamic localization in the human inferior parietal cortex in absence of amyloid plaques.

Publications

Amyloid β toxic conformer has dynamic localization in the human inferior parietal cortex in absence of amyloid plaques.

Similar Datasets

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