1. Academic Validation
  2. Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration

Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration

  • EBioMedicine. 2022 Apr;78:103970. doi: 10.1016/j.ebiom.2022.103970.
Qiuzhi Zhou 1 Shihong Li 1 Mengzhu Li 1 Dan Ke 1 Qun Wang 1 Ying Yang 1 Gong-Ping Liu 1 Xiao-Chuan Wang 1 Enjie Liu 2 Jian-Zhi Wang 3
Affiliations

Affiliations

  • 1 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 2 Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: liuenjie01@163.com.
  • 3 Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226000, China. Electronic address: wangjz@mail.hust.edu.cn.
Abstract

Background: Glycogen synthase kinase-3β (GSK-3β) is one of the most effective kinases in promoting tau hyperphosphorylation and accumulation in Alzheimer's disease (AD). However, it is not clear how GSK-3β activity is regulated during AD progression.

Methods: We firstly used mass spectrometry to identify the acetylation site of GSK-3β, and then established the cell and animal models of GSK-3β acetylation. Next, we conducted molecular, cell biological and behavioral tests. Finally, we designed a peptide to test whether blocking tau-mediated GSK-3β acetylation could be beneficial to AD.

Findings: We found that GSK-3β protein levels increased in the brains of AD patients and the transgenic mice. Overexpressing tau increased GSK-3β protein level with increased acetylation and decreased ubiquitination-related proteolysis. Tau could directly acetylate GSK-3β at K15 both in vitro and in vivo. K15-acetylation inhibited ubiquitination-associated proteolysis of GSK-3β and changed its activity-dependent phosphorylation, leading to over-activation of the kinase. GSK-3β activation by K15-acetylation in turn exacerbated the AD-like pathologies. Importantly, competitively inhibiting GSK-3β K15-acetylation by a novel-designed peptide remarkably improved cognitive impairment and the AD-like pathologies in 3xTg-AD mice.

Interpretation: Tau can directly acetylate GSK-3β at K15 which reveals a vicious cycle between tau hyperphosphorylation and GSK-3β activation.

Funding: This study was supported in parts by grants from Science and Technology Committee of China (2016YFC1305800), Hubei Province (2018ACA142), Natural Science Foundation of China (91949205, 82001134, 31730035, 81721005), Guangdong Provincial Key S&T Program (018B030336001).

Keywords

Acetylation; Alzheimer's disease; Glycogen synthase kinase-3β; Inhibitory peptide; Proteolysis; Tau.

Figures
Products
Inhibitors & Agonists
Other Products