Multiple roles for glycogen synthase kinase-3 as a drug target in Alzheimer's disease

Alzheimer's disease (AD) is a common neurodegenerative disorder that presents clinically as inexorable cognitive impairment and decline in performance of activities of daily living. AD is characterized pathologically by neuronal depopulation, extracellular amyloid plaques, and intraneuronal accumulation of neurofibrillary tangles (NFTs). Accumulation of these polypeptide aggregates is generally believed to be integral to the pathogenesis of AD. Recent evidence implicates the protein kinase glycogen synthase kinase 3 (GSK-3) in the regulation of both of these processes. GSK-3 has long been studied as one of several tau protein kinases, and has more recently been shown to be involved in the generation of Abeta peptides. GSK-3 activity may also promote cell death and conversely, inhibition of GSK-3 has been associated with increased cell survival under a variety of cytotoxic conditions. Thus drugs that target GSK-3 could attack AD pathogenesis on multiple fronts simultaneously. Here we will briefly review the molecular understanding of AD pathogenesis as it stands at this point, and then discuss the emerging role of GSK-3 in regulating these processes.