ALTERED OXIDATION AND SIGNAL-TRANSDUCTION SYSTEMS IN FIBROBLASTS FROMALZHEIMER PATIENTS

Abnormalities in calcium regulation, amyloid-beta-protein (A beta) pro duction and oxidative metabolism have been implicated in Alzheimer's d isease (AD). The use of cultured fibroblasts complement post-mortem an d genetic approaches in clarifying the interaction of these processes and the underlying mechanism for the changes in AD. Definition of gene defects in particular Alzheimer families (FAD) permits elucidation of the role of those genetic abnormalities in altered signal transductio n in cell lines from those families. Abnormalities in calcium regulati on, ion channels, cyclic AMP, the phosphatidylinositide cascade and ox idative metabolism are well documented in fibroblasts from patients wi th primary genetic defects in the presenilins. Recent studies in AD fi broblasts that demonstrate abnormal secretion of A beta, a protein kno wn to form the characteristic extracellular amyloid deposits in AD bra in, further supports the use of these cells in AD research. Comparison of changes in calcium signaling, mitochondrial oxidation and A beta p roduction in these cells suggests that changes in signal transduction including calcium may be a more consistent observation than altered A beta production in fibroblasts from some FAD families. An understandin g of these abnormalities in fibroblasts may provide further insights i nto the pathophysiology of AD, new diagnostic measures and perhaps inn ovative therapeutic approaches.