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CYP46A1-mediated ch...
CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice
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- Latorre-Leal, María (author)
- Karolinska Institutet
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- Rodriguez-Rodriguez, Patricia (author)
- Karolinska Institutet
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Franchini, Luca (author)
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Nikolidakis, Orestis (author)
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- Daniilidou, Makrina (author)
- Karolinska Institutet
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- Delac, Ljerka (author)
- Karolinska Institutet
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- Varshney, Mukesh K. (author)
- Karolinska Institutet
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Arroyo-García, Luis E. (author)
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- Eroli, Francesca (author)
- Karolinska Institutet
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- Winblad, Bengt (author)
- Karolinska Institutet
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- Blennow, Kaj, 1958 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Zetterberg, Henrik, 1973 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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Kivipelto, Miia (author)
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Pacciarini, Manuela (author)
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Wang, Yuqin (author)
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Griffiths, William J. (author)
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Björkhem, Ingemar (author)
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- Matton, Anna (author)
- Karolinska Institutet
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- Nalvarte, Ivan (author)
- Karolinska Institutet
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Merino-Serrais, Paula (author)
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- Cedazo-Minguez, Angel (author)
- Karolinska Institutet
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- Maioli, Silvia (author)
- Karolinska Institutet
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(creator_code:org_t)
- 2024
- 2024
- English.
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In: Science advances. - 2375-2548. ; 10:4
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Abstract
Subject headings
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- 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 5α-dihydrotestosterone in the hippocampus. We report that, in neurons, 24OH contributes to these divergent effects by activating sex hormone signaling, including estrogen receptors. CYP46A1 overexpression in female mice protects from memory impairments induced by ovariectomy while having no effects in gonadectomized males. Last, we measured cerebrospinal fluid levels of 24OH in a clinical cohort of patients with AD 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Latorre-Leal, Ma ...
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Rodriguez-Rodrig ...
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Franchini, Luca
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Nikolidakis, Ore ...
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Daniilidou, Makr ...
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Delac, Ljerka
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Varshney, Mukesh ...
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Arroyo-García, L ...
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Eroli, Francesca
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Winblad, Bengt
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Blennow, Kaj, 19 ...
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Zetterberg, Henr ...
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Kivipelto, Miia
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Pacciarini, Manu ...
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Wang, Yuqin
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Griffiths, Willi ...
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Björkhem, Ingema ...
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Matton, Anna
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Nalvarte, Ivan
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Merino-Serrais, ...
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Cedazo-Minguez, ...
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Maioli, Silvia
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Science advances
- By the university
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University of Gothenburg
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Karolinska Institutet