Sulfhydration Of Akt Triggers Tau-Phosphorylation By Activating Glycogen Synthase Kinase 3 Beta In Alzheimer'S Disease

In Alzheimer's disease (AD), human Tau is phosphorylated at S199 (hTau-S199-P) by the protein kinase glycogen synthase kinase 3 beta (GSK3 beta). HTau-S199-P mislocalizes to dendritic spines, which induces synaptic dysfunction at the early stage of AD. The AKT kinase, once phosphorylated, inhibits GSK3 beta by phosphorylating it at S9. In AD patients, the abundance of phosphorylated AKT with active GSK3 beta implies that phosphorylated AKT was unable to inactivate GSK3 beta. However, the underlying mechanism of the inability of phosphorylated AKT to phosphorylate GSK3 beta remains unknown. Here, we show that total AKT and phosphorylated AKT was sulfhydrated at C77 due to the induction of intracellular hydrogen sulfide (H2S). The increase in intracellular H2S levels resulted from the induction of the proinflammatory cytokine, IL-1 beta, which is a pathological hallmark of AD. Sulfhydrated AKT does not interact with GSK3 beta, and therefore does not phosphorylate GSK3 beta. Thus, active GSK3 beta phosphorylates Tau aberrantly. In a transgenic knockin mouse (AKT-KI+/+) that lacked sulfhydrated AKT, the interaction between AKT or phosphoAKT with GSK3 beta was restored, and GSK3 beta became phosphorylated. In AKT-KI+/+ mice, expressing the pathogenic human Tau mutant (hTau-P301L), the hTau S199 phosphorylation was ameliorated as GSK3 beta phosphorylation was regained. This event leads to a decrease in dendritic spine loss by reducing dendritic localization of hTau-S199-P, which improves cognitive dysfunctions. Sulfhydration of AKT was detected in the postmortem brains from AD patients; thus, it represents a posttranslational modification of AKT, which primarily contributes to synaptic dysfunction in AD.