The Role of Lipid Rafts on Androgen's Neurotoxic Effects

Abstract

Purpose: Vascular dementia (VaD) is a form of cognitive decline resulting from cerebrovascular disease in blood vessels. VaD is an age-related disease accounting for approximately 17-25% of cases of dementia, with men having a higher risk. Oxidative stress (OS) plays a large role in aging associated diseases, such as VaD. Using an in vitro model, our prior studies show androgens, the major male sex hormone, through an androgen receptor (AR) localized to lipid rafts in the plasma membrane exacerbates OS, which may worsen VaD. We seek to determine if interfering with AR localization to cholesterol-rich lipid rafts decreases androgen induced neurotoxicity. Methods: Since testosterone is only toxic under OS conditions, we exposed N27 cells to H2O2 (20 uM) to induce an OS condition followed by testosterone (100 nM). Nystatin (50 uM) was used to decrease cholesterol-rich lipid rafts that contain AR in order to block testosterone's damaging effects in an OS environment. The MTT assay was used to quantify cell viability. AR and lipid raft proteins were quantified. Results: Cholesterol inhibition using nystatin decreased both AR and lipid raft proteins. Nystatin blocked testosterone exacerbation of H2O2 induced cell loss. Conclusion: This study shows that the loss of lipid rafts via nystatin blocked androgen-induced OS in cells by altering the structure and function of AR. During VaD, neuronal dysfunction can impair cognition, thus this study suggests that repurposing statins for the treatment of VaD may be useful.