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.
Keywords: Alzheimer’s disease, glycogen synthase kinase 3, Aβ, tau hyperphosphorylation, neuroinflammation, apoptosis, Serine phosphorylation, neuronal cells.
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