Deposition of the beta-amyloid protein (Abeta) in the cerebral parenchyma and around blood vessels is a diagnostic hallmark of Alzheimer's disease (AD) and also occurs in aged primates and older individuals with Down's syndrome (trisomy 21). Abeta is derived from the amyloid precursor protein (APP), coded for by a gene on chromosome 21, that gives rise to transcripts coding for several APP isoforms, including APP-695 and -751. APP-695 is enriched in the brain, localized in neurons, and transported rapidly to nerve terminals; APP-751, which contains a protease inhibitor domain, is present in the brain and systemic organs. In transfected cells, APP isoforms are cleaved within the Abeta domain, an event that prevents the formation of Abeta. Failure of this cleavage and the occurrence of abnormal proteolytic processing could generate Abeta. Although the mechanisms of Abeta formation are not well understood, these processes can be examined in aged animals and in transgenic mice that show elevated levels of APP-751 or APP mutations linked to familial AD. We plan to investigate the levels of transgene expression and the character, distribution, and evolution of Abeta deposits in several lines of transgenic mice (i.e., animals overexpressing APP-751 and mice with APP mutations linked to AD). Levels of APP transcripts and the transport, distribution, and fate of APP isoforms will be analyzed in several neuronal systems in young and aged animals and, eventually, in transgenic mice. We hypothesize that animals with APP deposits will show abnormal cleavages of APP, a process that can only be directly examined by these in vivo investigations. These studies will enhance our understanding of the role of mutations in the pathogenesis of familial AD and the mechanisms of amyloidogenesis. This information is critical in the design of therapies to interfere with amyloidogenesis in patients with AD.
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