Beta-amyloid pathology in human brain microvessel extracts from the parietal cortex: relation with cerebral amyloid angiopathy and Alzheimer's disease

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 A 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 A 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 theneuropathological diagnosis of AD. Higher ELISA-determined concentrations of vascular A40 and A42 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 A clearance, ABCB1 and neprilysin, were lower in persons with AD and positively correlated with cognitive function, while being inversely correlated to vascular A40. In contrast, BACE1, a protein necessary for A production, was increased in individuals with AD and in apoE4 carriers, negatively correlated to cognitive function and positively correlated to A40 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 A and BACE1 and less ABCB1 and neprilysin, evidencing a pattern of dysfunction in brain microvascular cells contributing to CAA and AD pathology and symptoms.