Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

Abstract The role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis...

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Autores principales:	Vijay R. Varma, H. Büşra Lüleci, Anup M. Oommen, Sudhir Varma, Chad T. Blackshear, Michael E. Griswold, Yang An, Jackson A. Roberts, Richard O’Brien, Olga Pletnikova, Juan C. Troncoso, David A. Bennett, Tunahan Çakır, Cristina Legido-Quigley, Madhav Thambisetty
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Geriatrics RC952-954.6
Acceso en línea:	https://doaj.org/article/9b5faa98d6754c758ecbe26dd59288c8
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spelling	oai:doaj.org-article:9b5faa98d6754c758ecbe26dd59288c82021-12-02T18:24:51ZAbnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study10.1038/s41514-021-00064-92056-3973https://doaj.org/article/9b5faa98d6754c758ecbe26dd59288c82021-06-01T00:00:00Zhttps://doi.org/10.1038/s41514-021-00064-9https://doaj.org/toc/2056-3973Abstract The role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.Vijay R. VarmaH. Büşra LüleciAnup M. OommenSudhir VarmaChad T. BlackshearMichael E. GriswoldYang AnJackson A. RobertsRichard O’BrienOlga PletnikovaJuan C. TroncosoDavid A. BennettTunahan ÇakırCristina Legido-QuigleyMadhav ThambisettyNature PortfolioarticleGeriatricsRC952-954.6ENnpj Aging and Mechanisms of Disease, Vol 7, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Geriatrics RC952-954.6
spellingShingle	Geriatrics RC952-954.6 Vijay R. Varma H. Büşra Lüleci Anup M. Oommen Sudhir Varma Chad T. Blackshear Michael E. Griswold Yang An Jackson A. Roberts Richard O’Brien Olga Pletnikova Juan C. Troncoso David A. Bennett Tunahan Çakır Cristina Legido-Quigley Madhav Thambisetty Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study
description	Abstract The role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.
format	article
author	Vijay R. Varma H. Büşra Lüleci Anup M. Oommen Sudhir Varma Chad T. Blackshear Michael E. Griswold Yang An Jackson A. Roberts Richard O’Brien Olga Pletnikova Juan C. Troncoso David A. Bennett Tunahan Çakır Cristina Legido-Quigley Madhav Thambisetty
author_facet	Vijay R. Varma H. Büşra Lüleci Anup M. Oommen Sudhir Varma Chad T. Blackshear Michael E. Griswold Yang An Jackson A. Roberts Richard O’Brien Olga Pletnikova Juan C. Troncoso David A. Bennett Tunahan Çakır Cristina Legido-Quigley Madhav Thambisetty
author_sort	Vijay R. Varma
title	Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study
title_short	Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study
title_full	Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study
title_fullStr	Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study
title_full_unstemmed	Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study
title_sort	abnormal brain cholesterol homeostasis in alzheimer’s disease—a targeted metabolomic and transcriptomic study
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9b5faa98d6754c758ecbe26dd59288c8
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Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

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