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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.
Keywords: Alzheimer’s disease, glycogen synthase kinase 3, Aβ, tau hyperphosphorylation, neuroinflammation, apoptosis, Serine phosphorylation, neuronal cells.
Current Alzheimer Research
Title:Roles of Glycogen Synthase Kinase 3 in Alzheimer’s Disease
Volume: 9 Issue: 7
Author(s): Zhiyou Cai, Yu Zhao and Bin Zhao
Affiliation:
Keywords: Alzheimer’s disease, glycogen synthase kinase 3, Aβ, tau hyperphosphorylation, neuroinflammation, apoptosis, Serine phosphorylation, neuronal cells.
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.
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Cite this article as:
Cai Zhiyou, Zhao Yu and Zhao Bin, Roles of Glycogen Synthase Kinase 3 in Alzheimer’s Disease, Current Alzheimer Research 2012; 9 (7) . https://dx.doi.org/10.2174/156720512802455386
DOI https://dx.doi.org/10.2174/156720512802455386 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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