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CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice
María Latorre-Leal 
,
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
,
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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Copyright © 2024 The Authors, some rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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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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| ISSN: | 2375-2548 |
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American Association for the Advancement of Science (AAAS)
2024
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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
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v2 65333 2023-12-16 CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice 97e7258d0fe568df57f24c043f5f90cb Manuela Pacciarini Manuela Pacciarini true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false 2023-12-16 BMS 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. Journal Article Science Advances 10 4 American Association for the Advancement of Science (AAAS) 2375-2548 24 1 2024 2024-01-24 10.1126/sciadv.adj1354 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Other 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.) BB/S019588/1, BB/L001942/1 2024-04-07T13:04:15.0880312 2023-12-16T16:13:46.6300094 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science María Latorre-Leal 0000-0002-8434-3822 1 Patricia Rodriguez-Rodriguez 0000-0002-2438-3515 2 Luca Franchini 3 Orestis Nikolidakis 0009-0006-2685-8736 4 Makrina Daniilidou 5 Ljerka Delac 0000-0003-1840-1710 6 Mukesh K. Varshney 0000-0003-2165-0152 7 Luis E. Arroyo-García 0000-0002-9206-0179 8 Francesca Eroli 9 Bengt Winblad 0000-0002-0011-1179 10 Kaj Blennow 0000-0002-1890-4193 11 Henrik Zetterberg 0000-0003-3930-4354 12 Miia Kivipelto 0000-0003-0992-3875 13 Manuela Pacciarini 14 Yuqin Wang 0000-0002-3063-3066 15 William Griffiths 0000-0002-4129-6616 16 Ingemar Björkhem 17 Anna Matton 0000-0002-7819-0495 18 Ivan Nalvarte 0000-0001-6828-2583 19 Paula Merino-Serrais 0000-0002-1842-9476 20 Angel Cedazo-Minguez 0000-0003-4626-4864 21 Silvia Maioli 0000-0002-9577-0803 22 65333__29828__eb11e9f93d1b4a01947651520a37adb3.pdf 65333.VOR.pdf 2024-03-25T12:58:59.5108995 Output 10997853 application/pdf Version of Record true Copyright © 2024 The Authors, some rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. true eng https://creativecommons.org/licenses/by/4.0/ |
| title |
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice |
| spellingShingle |
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice Manuela Pacciarini Yuqin Wang William Griffiths |
| title_short |
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice |
| title_full |
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice |
| title_fullStr |
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice |
| title_full_unstemmed |
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice |
| title_sort |
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice |
| author_id_str_mv |
97e7258d0fe568df57f24c043f5f90cb c92729b58622f9fdf6a0e7d8f4ce5081 3316b1d1b524be1831790933eed1c26e |
| author_id_fullname_str_mv |
97e7258d0fe568df57f24c043f5f90cb_***_Manuela Pacciarini c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang 3316b1d1b524be1831790933eed1c26e_***_William Griffiths |
| author |
Manuela Pacciarini Yuqin Wang William Griffiths |
| author2 |
María Latorre-Leal 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 |
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Journal article |
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Science Advances |
| container_volume |
10 |
| container_issue |
4 |
| publishDate |
2024 |
| institution |
Swansea University |
| issn |
2375-2548 |
| doi_str_mv |
10.1126/sciadv.adj1354 |
| publisher |
American Association for the Advancement of Science (AAAS) |
| college_str |
Faculty of Medicine, Health and Life Sciences |
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|
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
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Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science |
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| description |
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. |
| published_date |
2024-01-24T13:04:12Z |
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11.014067 |