Sulfhydration of AKT triggers Tau-phosphorylation by activating glycogen synthase kinase 3β in Alzheimer’s disease

Significance It is well known that AKT inactivates glycogen synthase kinase 3β (GSK3β) by increasing its phosphorylation. The inactivation of GSK3β leads to aberrant phosphorylation of Tau, which is a hallmark of Alzheimer’s disease. However, we found that if phosphorylated AKT is sulfhydrated, it will be unable to inactivate GSK3β and subsequently increases Tau phosphorylation. The influence of sulfhydrated AKT on GSK3β and Tau phosphorylation was reversed in a transgenic AKT-KI +/+ mouse, where sulfhydration of AKT residue was mutated to alanine. Thus, AKT-sulfhydration represents a unique posttranslational modification of AKT that can be targeted to suppress phosphorylation of GSK3β and subsequently reduce Tau phosphorylation.