The GSK3 hypothesis of Alzheimer's disease

Abstract

Glycogen synthase kinase 3 (GSK3) is a constitutively active, proline-directed serine/threonine kinase that plays a part in a number of physiological processes ranging from glycogen metabolism to gene transcription. GSK3 also plays a pivotal and central role in the pathogenesis of both sporadic and familial forms of Alzheimer's disease (AD), an observation that has led us to coin the 'GSK3 hypothesis of AD'. According to this hypothesis, over-activity of GSK3 accounts for memory impairment, tau hyper-phosphorylation, increased beta-amyloid production and local plaque-associated microglial-mediated inflammatory responses; all of which are hallmark characteristics of AD. If our 'GSK3 hypothesis of AD' is substantiated and GSK3 is indeed a causal mediator of AD then inhibitors of GSK3 would provide a novel avenue for therapeutic intervention in this devastating disorder.

Fig. 1

GSK3 and its role in AD. Over-activity of GSK3 caused either by aberrant Wnt or insulin signaling in sporadic AD cases or through familial mutations in PS or APP in FAD, might play an integral role in disease progression. GSK3 mediates the hyper-phosphorylation of tau, the increased production of Aβ from APP (via β and γ secretase-mediated cleavage) and results in impairments in learning and memory and could potentially heighten microglial-mediated inflammatory responses in the local vicinity of Aβ plaques.