Abstract
Hyperphosphorylation of Tau and the ensuing microtubule destabilization are linked to synaptic dysfunction in Alzheimer's disease (AD). We find a marked increase of phosphorylated Tau (pTau) in cortical neurons differentiated from induced pluripotent stem cells (iPSCs) of AD patients. It is accompanied by significantly elevated expression of Serum and Glucocorticoid-regulated Kinase-1 (SGK1), which is induced by cellular stress, and Histone Deacetylase 6 (HDAC6), which deacetylates tubulin to destabilize microtubules. Indeed, acetylated tubulin and microtubule stability are significantly lower in AD-derived cortical neurons. SGK1 inhibitors or shRNA decrease Tau phosphorylation and HDAC6 levels while increasing acetylated tubulin in AD neurons. Overexpression of SGK1 in normal neurons does the opposite. These results suggest that elevation of the cellular stress-induced SGK1 increases Tau phosphorylation and HDAC6 expression, which destabilize microtubules to compromise many cellular functions subserving cognition. The coordinated increases in SGK1, pTau, and HDAC6, as well as the corresponding decrease in acetylated tubulin and microtubule stability in AD neurons, offer attractive targets for therapeutic development.