Exploring Whether Biological Sex Impacts the Effects of CYP46A1 Overexpression in a Mouse Model of Alzheimer's Disease

Abstract

The overexpression of cholesterol 24-hydroxylase (CYP46A1), an enzyme crucial for cholesterol turnover in the brain, has recently been explored as a potential therapeutic strategy for Alzheimer's disease (AD), given the linkage between cholesterol metabolism dysregulation in the brain and neurodegeneration. Promising results of improved memory performance and decreased disease hallmarks in AD mouse models have been described, but findings were limited to the use of female mice. A previous study from our group has shown that CYP46A1 overexpression in aged WT mice induces beneficial effects over neurodegenerative processes in females but detrimental repercussions in males. As biological sex is an important risk factor for AD, with about two-thirds of patients being women, sex differences must be considered when studying this pathology and searching for treatments. Therefore, we aim to further investigate whether the potential neuroprotective effects of CYP46A1 overexpression are also sex-dependent in the context of AD, using the APP NL-F knock-in mouse model for the purpose of the study.