Altered oxidation and signal transduction systems in fibroblasts from Alzheimer patients.
Abnormalities in calcium regulation, amyloid-beta-protein (A beta) production and oxidative metabolism have been implicated in Alzheimer's disease (AD). The use of cultured fibroblasts complement post-mortem and 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 transduction in cell lines from those families. Abnormalities in calcium regulation, ion channels, cyclic AMP, the phosphatidylinositide cascade and oxidative metabolism are well documented in fibroblasts from patients with primary genetic defects in the presenilins. Recent studies in AD fibroblasts that demonstrate abnormal secretion of A beta, a protein known to form the characteristic extracellular amyloid deposits in AD brain, further supports the use of these cells in AD research. Comparison of changes in calcium signaling, mitochondrial oxidation and A beta production 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 understanding of these abnormalities in fibroblasts may provide further insights into the pathophysiology of AD, new diagnostic measures and perhaps innovative therapeutic approaches.
Gibson
G
G
Cornell University Medical College, Burke Medical Research Institute, White Plains, NY 10605, USA.
Martins
R
R
Blass
J
J
Gandy
S
S
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D046508:Culture Techniques; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D002118:Calcium