SEX-SPECIFIC SIGNATURES OF <EM>CYP46A1</EM> OVEREXPRESSION IN <EM>APP</EM> KNOCK-IN MOUSE MODELS OF ALZHEIMER’S DISEASE PATHOLOGY DURING AGING

Altered brain cholesterol metabolism has been evidenced in aging and Alzheimer's Disease (AD). Postmortem AD brains show reduced 24(S)-hydroxycholesterol (24(S)-OH), a product of CYP46A1 enzymatic activity, essential for brain cholesterol turnover. Previously, we showed that CYP46A1 overexpression induces sex-specific effects and improves memory in aging and menopause-like conditions in female mice¹. Here, we explored whether CYP46A1 confers sex-specific neuroprotection against AD pathology.
We generated AD-like mouse models with enhanced brain cholesterol turnover. App knock-in mice carrying familial AD mutations (App^NL-F/NL-F and App^{NL-G-F/NL-G-F}) were each crossed with human CYP46A1-overexpressing mice (Cyp46Tg). Male and female offsprings (Cyp46TgxApp^NL-F/NL-F and Cyp46TgxApp^{NL-G-F/NL-G-F}) were analyzed at 6 (adult), 12 (middle-aged), and 20 months (aged mice).
CYP46A1 overexpression affected glial, oxysterol, and lipidomic profile in a sex- and age-dependent manner. Middle-aged Cyp46TgxApp^NL-F/NL-F mice of both sexes exhibited decreased hippocampal levels of Iba1. By 20 months, males showed decreased Iba1 and GFAP levels, whereas females showed reduced Iba1 immunoreactivity, indicating sex-specific glial responses over time. Lipidomic analysis revealed sex differences, including increased triglycerides in aged males. Aged females showed elevated carnitine levels, consistent with increased Cpt1c expression, involved in β-oxidation. In the App^{NL-G-F/NL-G-F} model, CYP46A1 overexpression restored 24(S)-OH levels and TG species in middle-aged females.
Overall, CYP46A1 overexpression differentially affects glial activation and lipid metabolism across sex and age in AD-like models, with female-specific effects associated with reduced neuroinflammation and improved cholesterol and lipid homeostasis. This underscores CYP46A1's therapeutic potential, particularly for women at increased AD risk or early disease stages.
¹Latorre Leal et al., Science Advances, 2024.