The role of lipid rafts in androgen's neurotoxic effects

Sex differences have been observed in multiple oxidative stress (OS) associated neurodegenerative diseases. Androgens, the major male sex hormone, through a membrane androgen receptor (mAR) localized to lipid rafts in the plasma membrane exacerbates OS. The goal of this study is to determine if interfering with mAR localization to cholesterol-rich lipid rafts decreases androgen induced neurotoxicity under OS environments. We hypothesize that cholesterol-rich caveolar lipid rafts are necessary for androgens to induce OS generation in neurons via the mAR localized within the plasma membrane. Nystatin was used to deplete cholesterol-rich caveolar lipid rafts in N27 cells prior to testosterone exposure in oxidative stressed N27 cells. Cell viability and protein analysis of OS, apoptosis, and mAR localization were conducted. Our results show that the loss of lipid rafts blocked androgen-induced OS in cells by decreasing the localization of mAR to caveolar lipid rafts. These results are consistent with our clinical findings that showed a relationship between hyperlipidemia and androgens on dementia in men but not women.