GSK3 in Alzheimer's disease: mind the isoforms

Understanding the molecular signaling pathways that go awry in Alzheimer's disease (AD) would provide insights into developing novel therapies for this devastating neurodegenerative disease. Previous work has established that hyperactive glycogen synthase kinase-3 (GSK3) is linked to both "sporadic" and "genetic" forms of AD, suggesting a crucial role of GSK3 in AD pathogenesis. Therefore, inhibition of GSK3 activity has been intensely investigated as a potential therapeutic intervention for AD. GSK3 exists in two isoforms: GSK3α and GSK3β. Markedly, recent studies indicate specific contributions of each of the α and β isoforms of GSK3 to AD pathogenesis, suggesting a role of both isoforms in the disease. Here I review recent relevant work investigating isoform-specific roles of GSK3 in AD pathophysiology, highlighting the emerging role of GSK3α, which has been largely overlooked in favor of the more extensive studies of GSK3β.