Cerebral amyloid angiopathy involving large and small vessels of the brain is common in Alzheimer's disease (AD), Down's syndrome and some related disorders. It is not known how amyloid deposits in the vessels. The long-range goal of this proposal is to elucidate the mechanisms by which amyloid deposition occurs in cerebral microvessels and arterioles in subjects with AD and related disorders, and to determine if such deposition is associated with abnormalities in the vasculature that may relate to the cause or contribute to the pathogenesis of AD. To address these questions, however, it is first vital to know the extent and rate at which amyloid deposition occurs in cerebral vessels during aging and disease and with what principal structures of the endothelium or vessel is the amyloid protein localized. The amyloid beta/A4 protein common to many diseases is derived from a membrane associated precursor protein (APP). Is this protein a normal constituent of the vessel, if so with which subcellular vascular compartment(s) is it associated and is there any evidence of differences in tissue-specific processing between AD subjects and aging controls? Furthermore, is vascular amyloid deposition related to changes in basement membrane components such as collagen IV or the glycosoaminoglycans of the cerebral endothelium? To investigate these issues, the investigators propose to employ relatively simple in vitro studies using biochemical and immunochemical methods on isolated cerebral capillaries and arterioles obtained postmortem from cortex of AD subjects and aged and young controls without evidence for neurological disease. Monoclonal and polyclonal antibodies to beta-protein and to various peptide fragments of APP will be used to probe immunoblots of vessel fractions and isolated vessel preparations. Assay of isolated vessels and their subcellular fractions will permit considerably better resolution of detection and metabolism of amyloid proteins than gained from this project will help in better understanding the pathogenesis of AD and related disorders and provide therapeutic approaches.
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