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CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice
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Patricia Rodriguez-Rodriguez ,
Luca Franchini,
Orestis Nikolidakis ,
Makrina Daniilidou,
Ljerka Delac ,
Mukesh K. Varshney ,
Luis E. Arroyo-García ,
Francesca Eroli,
Bengt Winblad ,
Kaj Blennow ,
Henrik Zetterberg ,
Miia Kivipelto ,
Manuela Pacciarini,
Yuqin Wang ,
William Griffiths ,
Ingemar Björkhem,
Anna Matton ,
Ivan Nalvarte ,
Paula Merino-Serrais ,
Angel Cedazo-Minguez ,
Silvia Maioli
Science Advances, Volume: 10, Issue: 4
Swansea University Authors:
Manuela Pacciarini, Yuqin Wang , William Griffiths
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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...
| Published in: | Science Advances |
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| ISSN: | 2375-2548 |
| Published: |
American Association for the Advancement of Science (AAAS)
2024
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| Online Access: |
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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. |
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| 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 |