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

María Latorre-Leal Orcid Logo, Patricia Rodriguez-Rodriguez Orcid Logo, Luca Franchini, Orestis Nikolidakis Orcid Logo, Makrina Daniilidou, Ljerka Delac Orcid Logo, Mukesh K. Varshney Orcid Logo, Luis E. Arroyo-García Orcid Logo, Francesca Eroli, Bengt Winblad Orcid Logo, Kaj Blennow Orcid Logo, Henrik Zetterberg Orcid Logo, Miia Kivipelto Orcid Logo, Manuela Pacciarini, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo, Ingemar Björkhem, Anna Matton Orcid Logo, Ivan Nalvarte Orcid Logo, Paula Merino-Serrais Orcid Logo, Angel Cedazo-Minguez Orcid Logo, Silvia Maioli Orcid Logo

Science Advances, Volume: 10, Issue: 4

Swansea University Authors: Manuela Pacciarini, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo

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DOI (Published version): 10.1126/sciadv.adj1354

Abstract

The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24S-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced CYP46A1 levels are observed in Alzheimer’s Disease (AD). In this study, we report that CYP46A1 overexpression in aged...

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Published in: Science Advances
ISSN: 2375-2548
Published: American Association for the Advancement of Science (AAAS) 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa65333
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Abstract: The brain-specific enzyme CYP46A1 controls cholesterol turnover by converting cholesterol into 24S-hydroxycholesterol (24OH). Dysregulation of brain cholesterol turnover and reduced CYP46A1 levels are observed in Alzheimer’s Disease (AD). In this study, we report that CYP46A1 overexpression in aged female mice leads to enhanced estrogen signaling in the hippocampus and improved cognitive functions. In contrast, age-matched CYP46A1 overexpressing males show anxiety-like behavior, worsened memory, and elevated levels of 5-dihydrotestosterone in the hippocampus. We report that in neurons 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. Indeed, CYP46A1 overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Finally, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of AD patients 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.
College: Faculty of Medicine, Health and Life Sciences
Funders: This work was supported by Margaretha af Ugglas Foundation (to A.C.-M., S.M., M.L.-L., P.R.-R., and F.E.); King Gustaf V:s and Queen Victorias Foundation (to S.M.); The private initiative “Innovative ways to fight Alzheimer’s disease - Leif Lundblad Family and others” (to S.M.); National Institute On Aging of the National Institutes of Health under Award Number R01AG065209 (to I.N., S.M., M.L.-L., and L.D.); The regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet nr 512578 (to S.M., A.C.-M., and F.E.); KID funding (to S.M. and L.D.); Gun och Bertil Stohnes Stiftelse (to S.M., P.R.-R., L.D., M.L.-L., A.C.-M., P.M.-S., A.M., M.D., and L.E.A.-G.), Karolinska Institutet Foundation for geriatric research (to S.M.); Stiftelsen Gamla Tjänarinnor (to S.M., P.R.-R., L.D., M.L.-L., A.C.-M., P.M.-S., A.M., M.D., and L.E.A.-G.); Tore Nilsson Stiftelse (to S.M.); EMBO long term Fellowship ALFT 696-2013, and the SSMF postdoctoral Fellowship (to P.M.-S.); and The Biotechnology and Biological Sciences Research Council BB/S019588/1 and BB/L001942/1 (to W.J.G. and Y.W.)
Issue: 4