Protein kinase C and amyloid precursor protein processing in skin fibroblasts from sporadic and familial Alzheimer's disease cases

Non-amyloidogenic alpha-secretase processing of amyloid precursor protein ( APP) is stimulated by protein kinase C (PKC). Levels and activity of PKC ar e decreased in sporadic Alzheimer's disease skin fibroblasts. We investigat ed whether alterations in PKC and PKC-mediated APP processing occur also in fibroblasts established from individuals with familial Alzheimer's disease APP KM670/671NL, PS1 M146V and H163Y mutations. These pathogenic mutations are known to alter APP metabolism to increase AP. PKC activities, but not levels, were decreased by 50% in soluble fractions from sporadic Alzheimer' s disease cases. In contrast, familial Alzheimer's disease fibroblasts show ed no significant changes in PKC enzyme activity. Fibroblasts bearing the A PP KM670/671NL mutation showed no significant differences in either PKC lev els or PKC-mediated soluble APP (APPs) secretion, compared to controls. Fib roblasts bearing PS1 M146V and H163Y mutations showed a 30% increase in sol uble PKC levels and a 40% decrease in PKC-mediated APPs secretion. These re sults indicate that PKC deficits are unlikely to contribute to increased AP seen with APP and PS1 mutations, and also that PS1 mutations decrease alph a-secretase derived APPs production independently of altered PKC activity. (C) 1999 Elsevier Science B.V. All rights reserved.