| First Author | Zhou Q | Year | 2022 |
| Journal | EBioMedicine | Volume | 78 |
| Pages | 103970 | PubMed ID | 35339896 |
| Mgi Jnum | J:322782 | Mgi Id | MGI:7258820 |
| Doi | 10.1016/j.ebiom.2022.103970 | Citation | Zhou Q, et al. (2022) Human tau accumulation promotes glycogen synthase kinase-3beta acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration. EBioMedicine 78:103970 |
| abstractText | BACKGROUND: Glycogen synthase kinase-3beta (GSK-3beta) 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-3beta activity is regulated during AD progression. METHODS: We firstly used mass spectrometry to identify the acetylation site of GSK-3beta, and then established the cell and animal models of GSK-3beta acetylation. Next, we conducted molecular, cell biological and behavioral tests. Finally, we designed a peptide to test whether blocking tau-mediated GSK-3beta acetylation could be beneficial to AD. FINDINGS: We found that GSK-3beta protein levels increased in the brains of AD patients and the transgenic mice. Overexpressing tau increased GSK-3beta protein level with increased acetylation and decreased ubiquitination-related proteolysis. Tau could directly acetylate GSK-3beta at K15 both in vitro and in vivo. K15-acetylation inhibited ubiquitination-associated proteolysis of GSK-3beta and changed its activity-dependent phosphorylation, leading to over-activation of the kinase. GSK-3beta activation by K15-acetylation in turn exacerbated the AD-like pathologies. Importantly, competitively inhibiting GSK-3beta 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-3beta at K15 which reveals a vicious cycle between tau hyperphosphorylation and GSK-3beta 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). |
