Androgens regulate neprilysin expression: role in reducing beta-amyloid levels

摘要

Age-related testosterone depletion in men is a risk factor for Alzheimer's disease. Prior studies suggest that androgens affect Alzheimer's disease risk by regulating accumulation of (3-amyloid protein (Ap) by an undefined mechanism. In this study, we investigated the role of the Ap-catabolizing enzyme neprilysin (NEP) in this process. First, we observed that androgens positively regulate neural expression of NEP in adult male rats. Next, we investigated androgen regulatory effects on both NEP expression and Ap levels using cultured hippocampal neurons and neuronally differentiated rat pheo-chromocytorna cell 12 with or without androgen receptor (AR). Dihydrotestosterone (DHT) induced a time-dependent increase in NEP expression. DHT also significantly decreased levels of Ap in AR-expressing cells transfected with amyloidprecursor protein, but did not affect levels of either full-length or non-amyloidogenic, soluble amyloid precursor protein. Importantly, the DHT induced decrease of Ap was blocked by pharmacological inhibition of NEP. The DHT-mediated increase in NEP expression and decrease in Ap levels were (i) not observed in rat pheochromocytoma cell 12 lacking AR and (ii) blocked in AR-expressing cells by the antagonists, cypro-terone acetate and flutamide. Together, these findings suggest that androgen regulation of Ap involves an AR-dependent mechanism requiring up-regulation of the Ap catabolizing enzyme NEP.