GSK-3 is essential in the pathogenesis of Alzheimer's disease

Article type: Research Article

Authors: Takashima, Akihiko

Affiliations: Laboratory for Alzheimer's Disease, Riken, Brain Science Institute, 2-1 Hirosawa, Wako-si, Saitama 351-0198, Japan. E-mail: [email protected]

Abstract: Glycogen synthase kinase-3 (GSK-3) is a pivotal molecule in the development of Alzheimer's disease (AD). GSK-3β is involved in the formation of paired helical filament (PHF)-tau, which is an integral component of the neurofibrillary tangle (NFT) deposits that disrupt neuronal function, and a marker of neurodegeneration in AD. GSK-3β has exactly the same oligonucleotide sequence as tau-protein kinase I (TPKI), which was first purified from the microtubule fraction of bovine brain. Initially, we discovered that GSK-3β was involved in amyloid-β (Aβ)-induced neuronal death in rat hippocampal cultures. In the present review, we discuss our initial in vitro results and additional investigations showing that Aβ activates GSK-3β through impairment of phosphatidylinositol-3 (PI3)/Akt signaling; that Aβ-activated GSK-3β induces hyperphosphorylation of tau, NFT formation, neuronal death, and synaptic loss (all found in the AD brain); that GSK-3β can induce memory deficits in vivo; and that inhibition of GSK-3α (an isoform of GSK-3β) reduces Aβ production. These combined results strongly suggest that GSK-3 activation is a critical step in brain aging and the cascade of detrimental events in AD, preceding both the NFT and neuronal death pathways. Therefore, therapeutics targeted to inhibiting GSK-3 may be beneficial in the treatment of this devastating disease.

Keywords: GSK-3β, NFT, Aβ, AD, tauopathy

DOI: 10.3233/JAD-2006-9S335

Journal: Journal of Alzheimer's Disease, vol. 9, no. s3, pp. 309-317, 2006