Abnormal brain cholesterol homeostasis in Alzheimer's disease-a targeted metabolomic and transcriptomic study.

IF 5.4 Q1 GERIATRICS & GERONTOLOGY
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
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引用次数: 48

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.

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阿尔茨海默病的异常脑胆固醇稳态-一项靶向代谢组学和转录组学研究
脑胆固醇代谢在阿尔茨海默病(AD)中的作用尚不清楚。由于血脑屏障(BBB)的不渗透性,外周和脑胆固醇水平在很大程度上是独立的,这突出了研究脑胆固醇稳态在AD中的作用的重要性。我们首先在巴尔的摩衰老纵向研究(BLSA)和宗教秩序研究(ROS)的两个脑尸检样本中使用线性混合效应模型测试了脑胆固醇生物合成和分解代谢的代谢物标志物是否在AD中改变并与AD病理相关。接下来,我们使用公开的脑组织转录组数据集的方差分析测试了AD患者脑胆固醇生物合成和分解代谢的遗传调节因子是否改变。最后,利用区域脑转录组学数据,我们进行了基因组尺度的代谢网络建模,以评估AD患者胆固醇生物合成和分解代谢反应的变化。我们发现AD与胆固醇生物合成和分解代谢的普遍异常有关。利用帕金森病(PD)脑组织样本的转录组学数据,我们发现在AD中发现的基因表达改变在PD中没有观察到,这表明这些变化可能是AD特异性的。我们的研究结果表明,阿尔茨海默病患者脑内胆固醇水平维持的酶促胆固醇分解代谢和外排受损,可能会导致新生胆固醇生物合成减少。这伴随着非酶促生成的细胞毒性氧甾醇的积累。我们的结果为实验研究奠定了基础,以解决胆固醇代谢异常是否可能是AD的治疗靶点。
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来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
自引率
0.00%
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0
审稿时长
8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
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