Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis

Afroditi Tsitsou-Kampeli; Stefano Suzzi; Mor Kenigsbuch; Akisawa Satomi; Romano Strobelt; Oded Singer; Ester Feldmesser; Maitreyee Purnapatre; Sarah Phoebeluc Colaiuta; Eyal David; Liora Cahalon; Oliver Hahn; Tony Wyss-Coray; Yosef Shaul; Ido Amit; Michal Schwartz

doi:10.1016/j.xcrm.2023.101278

Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis

Afroditi Tsitsou-Kampeli, Stefano Suzzi, Mor Kenigsbuch, Akisawa Satomi, Romano Strobelt, Oded Singer, Ester Feldmesser, Maitreyee Purnapatre, Sarah Phoebeluc Colaiuta, Eyal David, Liora Cahalon, Oliver Hahn, Tony Wyss-Coray, Yosef Shaul, Ido Amit, Michal Schwartz

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

Abstract

The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions. In vitro, the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) downregulates CYP46A1 expression, while overexpression of CYP46A1 or its pharmacological activation in mouse CP organ cultures increases resilience to TNF-α. In vivo, overexpression of CYP46A1 in the CP in transgenic mice with amyloidosis is associated with better cognitive performance and decreased brain inflammation. Our findings suggest that CYP46A1 expression in the CP impacts the role of this niche as a guardian of brain immune homeostasis.

Original language	English
Article number	101278
Number of pages	24
Journal	Cell Reports Medicine
Volume	4
Issue number	11
DOIs	https://doi.org/10.1016/j.xcrm.2023.101278
State	Published - 21 Nov 2023

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.xcrm.2023.101278

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Tsitsou-Kampeli, A., Suzzi, S., Kenigsbuch, M., Satomi, A., Strobelt, R., Singer, O., Feldmesser, E., Purnapatre, M., Colaiuta, S. P., David, E., Cahalon, L., Hahn, O., Wyss-Coray, T., Shaul, Y., Amit, I., & Schwartz, M. (2023). Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis. Cell Reports Medicine, 4(11), Article 101278. https://doi.org/10.1016/j.xcrm.2023.101278

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title = "Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis",

abstract = "The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions. In vitro, the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) downregulates CYP46A1 expression, while overexpression of CYP46A1 or its pharmacological activation in mouse CP organ cultures increases resilience to TNF-α. In vivo, overexpression of CYP46A1 in the CP in transgenic mice with amyloidosis is associated with better cognitive performance and decreased brain inflammation. Our findings suggest that CYP46A1 expression in the CP impacts the role of this niche as a guardian of brain immune homeostasis.",

author = "Afroditi Tsitsou-Kampeli and Stefano Suzzi and Mor Kenigsbuch and Akisawa Satomi and Romano Strobelt and Oded Singer and Ester Feldmesser and Maitreyee Purnapatre and Colaiuta, {Sarah Phoebeluc} and Eyal David and Liora Cahalon and Oliver Hahn and Tony Wyss-Coray and Yosef Shaul and Ido Amit and Michal Schwartz",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = nov,

day = "21",

doi = "10.1016/j.xcrm.2023.101278",

language = "الإنجليزيّة",

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journal = "Cell Reports Medicine",

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Tsitsou-Kampeli, A, Suzzi, S, Kenigsbuch, M, Satomi, A, Strobelt, R, Singer, O, Feldmesser, E, Purnapatre, M, Colaiuta, SP, David, E, Cahalon, L, Hahn, O, Wyss-Coray, T, Shaul, Y, Amit, I & Schwartz, M 2023, 'Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis', Cell Reports Medicine, vol. 4, no. 11, 101278. https://doi.org/10.1016/j.xcrm.2023.101278

TY - JOUR

T1 - Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis

AU - Tsitsou-Kampeli, Afroditi

AU - Suzzi, Stefano

AU - Kenigsbuch, Mor

AU - Satomi, Akisawa

AU - Strobelt, Romano

AU - Singer, Oded

AU - Feldmesser, Ester

AU - Purnapatre, Maitreyee

AU - Colaiuta, Sarah Phoebeluc

AU - David, Eyal

AU - Cahalon, Liora

AU - Hahn, Oliver

AU - Wyss-Coray, Tony

AU - Shaul, Yosef

AU - Amit, Ido

AU - Schwartz, Michal

PY - 2023/11/21

Y1 - 2023/11/21

N2 - The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions. In vitro, the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) downregulates CYP46A1 expression, while overexpression of CYP46A1 or its pharmacological activation in mouse CP organ cultures increases resilience to TNF-α. In vivo, overexpression of CYP46A1 in the CP in transgenic mice with amyloidosis is associated with better cognitive performance and decreased brain inflammation. Our findings suggest that CYP46A1 expression in the CP impacts the role of this niche as a guardian of brain immune homeostasis.

AB - The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions. In vitro, the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) downregulates CYP46A1 expression, while overexpression of CYP46A1 or its pharmacological activation in mouse CP organ cultures increases resilience to TNF-α. In vivo, overexpression of CYP46A1 in the CP in transgenic mice with amyloidosis is associated with better cognitive performance and decreased brain inflammation. Our findings suggest that CYP46A1 expression in the CP impacts the role of this niche as a guardian of brain immune homeostasis.

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U2 - 10.1016/j.xcrm.2023.101278

DO - 10.1016/j.xcrm.2023.101278

M3 - مقالة

C2 - 37944529

SN - 2666-3791

VL - 4

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 11

M1 - 101278

ER -

Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis

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