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

作者：Vijay R. Varma, Hatice Büşra Lüleci̇, Anup Mammen Oommen, Sudhir Varma, Chad Blackshear, Michael Griswold, Yang An, Jackson A. Roberts, Richard O’Brien, Olga Pletniková, Juan C. Troncoso, David A. Bennett, Tunahan Çakır, Cristina Legido‐Quigley, Madhav Thambisetty · 发表于：npj Aging and Mechanisms of Disease · 年份：2021 · DOI：10.1038/s41514-021-00064-9 · 被引用次数：156 · 研究领域：Metabolomics and Mass Spectrometry Studies、Cholesterol and Lipid Metabolism、Computational Drug Discovery Methods

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...