Akt/GSK3β serine/threonine kinases: evidence for a signalling pathway mediated by familial Alzheimer's disease mutations

Abstract

Although Alzheimer's disease pathologically affects the brain, familial Alzheimer's disease associated mutations of β-amyloid precursor protein and presenilin are ubiquitously expressed and therefore aberrant intracellular signals, separate from but similar to, the brain may be expected. Here, we report selective down regulation of the serine/threonine kinase, Akt/PKB, concurrent with elevated endogenous GSK3β kinase activity in familial Alzheimer's disease β-amyloid precursor protein expressing human embryonic kidney (HEK) and familial Alzheimer's disease presenilin lymphoblast cells. Further, familial Alzheimer's disease presenilin in the human lymphoblast was associated with β-catenin destabilization. Moreover, limited immunohistochemistry analysis reveals Akt/PKB in a subset of neurofibrillary tangles where GSK3β and τ have been reported to co-localize, suggesting a possible Akt/GSK3β and τ interaction in vivo. Our data suggest that familial Alzheimer's disease mutants of β-amyloid precursor protein and presenilin signal, at least in part, through the Akt/GSKβ pathway and that Akt/GSK3β-mediated signalling may contribute to the underlying Alzheimer's disease pathogenesis induced by familial Alzheimer's disease mutants.