Roles of Glycogen Synthase Kinase 3 in Alzheimer's Disease

Evidence from basic molecular biology has noted a critical role of GSK-3 in Alzheimer's disease (AD) pathogenesis such as beta-amyloid (A beta) production and accumulation, the formation of neurofibrillary tangle (NFT), and neuronal degeneration. A beta generation and deposition represents a key feature and is generated from APP by the sequential actions of two proteolytic enzymes: beta-secretase and gamma-secretase. GSK-3 could play a critical role in A beta production via enhancing beta-secretase activity. GSK-3 not only modulates APP processing in the process of A beta generation, but regulates A beta production by interfering with APP cleavage at the gamma-secretase complex step since the APP and PS1 (a component of gamma-secretase complex) are substrates of GSK-3 as well. GSK-3 may downregulate alpha-secretase through inhibiting PKC and ADAMs activity which are the substrates of GSK-3 contributing to A beta production. Meanwhile, A beta accumulation can induce GSK-3 activation through A beta-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-3 beta 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.