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.

journal_name

Curr Alzheimer Res

authors

Cai Z,Zhao Y,Zhao B

doi

10.2174/156720512802455386

subject

Has Abstract

pub_date

2012-09-01 00:00:00

pages

864-79

issue

7

eissn

1567-2050

issn

1875-5828

pii

CAR-EPUB-20120123-020

journal_volume

9

pub_type

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