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

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).