Aberrant amyloid beta-protein precursor (ABPP) metabolism is probably a major early event in Alzheimer's disease (AD) pathogenesis leading to amyloid plaques. We and others have identified two major pathways for ABPP metabolism, viz. secretion and lysosomal degradation. Secretion involves cleavage from the membrane form to release a soluble, shorter N-terminal ABPP and a small membrane C-terminal reactive form. We do not yet know where normal cleavage is in relation to the beta-protein region, nor what processes are involved in regulating secretion v.s. putative lysosomal degradation. We have recently discovered that ABPP is regulated by fibroblast basic growth factor (FGF) and that FGF is elevated in AD brain and abnormally distributed in and around plaques suggesting a possible role in putative plaque-associated abnormalities in ABPP. We have recently reported preliminary evidence for reduced ABPP mRNA and ABPP release in cultured familial Alzheimer disease fibroblasts. Although the ABPP gene and a familial Alzheimer's disease (FAD) gene are both located on chromosome 21, it is not known whether the FAD gene modulates ABPP mRNA expression or ABPP metabolism. The proposed studies are designed to investigate these problems in genetically engineered human neuronal and fibroblast cell lines and in AD and control fibroblasts.
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