CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice.

Abstract

The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24<i>S</i>-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced <i>CYP46A1</i> levels are observed in Alzheimer's disease (AD). In this study, we report that <i>CYP46A1</i> overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched <i>CYP46A1</i> overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. <i>CYP46A1</i> overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD and found that 24OH negatively correlates with neurodegeneration markers only in women. We suggest that CYP46A1 activation is a valuable pharmacological target for enhancing estrogen signaling in women at risk of developing neurodegenerative diseases.