Androgens Regulate Tau Phosphorylation Through Phosphatidylinositol 3-Kinase-Protein Kinase B-Glycogen Synthase Kinase 3β Signaling

Age-related testosterone depletion in men is a risk factor for Alzheimer's disease (AD). How testosterone modulates AD risk remains to be fully elucidated, although regulation of tau phosphorylation has been suggested as a contributing protective action. To investigate the relationship between testosterone and tau phosphorylation, we first evaluated the effect of androgen status on tau phosphorylation in 3xTg-AD mice. Depletion of endogenous androgens via gonadectomy resulted in increased tau phosphorylation that was prevented by acute testosterone treatment. Parallel alterations in the phosphorylation of both glycogen synthase kinase 3(3 (GSK3(3) and protein kinase B (Akt) suggest possible components of the underlying signaling pathway. To further explore mechanism, primary cultured neurons were treated with a physiological concentration of testosterone or its active metabolite dihydrotestosterone (DHT). Results showed that testosterone and DHT induced significant decreases in phosphorylated tau and significant increases in phosphorylation of Akt and GSK3(3. Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) effectively inhibited androgen-induced increases in Akt and GSK3(3 phosphorylation, and decreases in tau phosphorylation. In addition, androgen receptor (AR) knock-down by small interfering RNA prevented androgen-induced changes in the phosphorylation of Akt, GSK3(3 and tau, suggesting an AR-dependent mechanism. Additional experiments demonstrated androgen-induced changes in Akt, GSK3(3 and tau phosphorylation in AR-expressing PC12 cells but not in AR-negative PC12 cells. Together, these results suggest an AR-dependent pathway involving PI3K-Akt-GSK3(3 signaling through which androgens can reduce tau phosphorylation. These findings identify an additional protective mechanism of androgens that can improve neural health and inhibit development of AD.(c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.