title: Roles of glycogen synthase kinase 3 in Alzheimer's disease.
abstract: Evidence from basic molecular biology has noted a critical role of GSK-3 in Alzheimer's disease (AD) pathogenesis such as beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangle (NFT), and neuronal degeneration. Aβ generation and deposition represents a key feature and is generated from APP by the sequential actions of two proteolytic enzymes: β-secretase and γ-secretase. GSK-3 could play a critical role in Aβ production via enhancing β-secretase activity. GSK-3 not only modulates APP processing in the process of Aβ generation, but regulates Aβ production by interfering with APP cleavage at the γ-secretase complex step since the APP and PS1 (a component of γ- secretase complex) are substrates of GSK-3 as well. GSK-3 may downregulate α-secretase through inhibiting PKC and ADAMs activity which are the substrates of GSK-3 contributing to Aβ production. Meanwhile, Aβ accumulation can induce GSK-3 activation through Aβ-mediated neuroinflammation and oxidative stress. Considering that active GSK-3 and some common GSK-3-shared factors induce the hyperphosphorylation of tau and neurofibrillary lesions, GSK-3 is a possible linking between amyloid plaques and NFT pathology. Additionally, GSK-3 could disrupt acetylcholine activity, and accelerate axon degeneration and failures in axonal transport, and lead to cognitive impairment in AD. Preclinical and clinical studies have supported that GSK-3β inhibitors could be useful in the treatment of AD. Consequently, an effective measure to inhibit GSK-3 activity may be a very attractive drug target in AD.
authors.affiliation: Department of Pharmaceutical Sciences, Texas A&M Health Science Center, Kingsville, Texas 78363, USA.
authors.forename: Zhiyou
authors.initials: Z
authors.lastname: Cai
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases