Affiliation:
1. School of Basic Medical Sciences Zhejiang Chinese Medical University Hangzhou China
2. College of Pharmaceutical Sciences Zhejiang University Hangzhou China
3. Future Health Laboratory, Innovation Center of Yangtze River Delta Zhejiang University Jiaxing China
4. Cangnan County Qiushi Innovation Research Institute of Traditional Chinese Medicine Wenzhou China
5. Key Laboratory of Blood‐stasis‐toxin Syndrome of Zhejiang Province Hangzhou China
Abstract
AbstractGlycogen synthase kinase‐3 (GSK3), consisting of GSK3α and GSK3β subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aβ aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aβ formation, and directly or indirectly triggers neuroinflammation and oxidative damage. We also summarize preclinical research highlighting the inhibition of GSK3 activity as a primary therapeutic approach for AD. Finally, pending issues like the lack of highly specific and affinity‐driven GSK3 inhibitors, are raised and expected to be addressed in future research. In conclusion, GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Zhejiang Province