GSK-3 is essential in the pathogenesis of Alzheimer's disease.
Glycogen synthase kinase-3 (GSK-3) is a pivotal molecule in the development of Alzheimer's disease (AD). GSK-3beta 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-3beta 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-3beta was involved in amyloid-beta (Abeta)-induced neuronal death in rat hippocampal cultures. In the present review, we discuss our initial in vitro results and additional investigations showing that Abeta activates GSK-3beta through impairment of phosphatidylinositol-3 (PI3)/Akt signaling; that Abeta-activated GSK-3beta induces hyperphosphorylation of tau, NFT formation, neuronal death, and synaptic loss (all found in the AD brain); that GSK-3beta can induce memory deficits in vivo; and that inhibition of GSK-3alpha (an isoform of GSK-3beta) reduces Abeta 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.
Takashima
Akihiko
A
Laboratory for Alzheimer's Disease, Riken, Brain Science Institute, 2-1 Hirosawa, Wako-si, Saitama 351-0198, Japan. kenneth@brain.riken.go.jp
D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D001921:Brain / Q000201:enzymology* / Q000473:pathology*; D003072:Cognition Disorders / Q000150:complications; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D016874:Neurofibrillary Tangles / Q000473:pathology; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3