胆固醇和他汀类药物的细胞生化:阿尔茨海默病的病理生理学和治疗的见解

Benjamin Wolozin, James Brown III, Catherine Theisler, Simone Silberman
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引用次数: 50

摘要

迟发性阿尔茨海默病(AD)的病因尚不清楚。虽然β-淀粉样蛋白(a β)被认为在阿尔茨海默病的病理生理中起着关键作用,但没有遗传证据直接表明a β与晚发性阿尔茨海默病有关。这表明,与AD相关的Aβ积累和神经变性可能是由间接影响Aβ产生或积累的异常引起的。越来越多的证据表明,胆固醇和相关分子(如胆固醇酯和24(S)羟基胆固醇)代谢异常可能通过增加Aβ的产生而参与晚发型AD的病理生理。24(S)羟胆固醇是氧化胆固醇分解代谢物家族的一员,被称为氧甾醇,其功能是调节胆固醇从细胞的输出和胆固醇代谢相关基因的转录。胆固醇酯是用于储存胆固醇的胆固醇衍生物。24(S)羟基胆固醇水平随AD升高而升高。对胆固醇生理有重要影响的几个不同基因的多态性与AD中Aβ负荷或水平的增加有关。这些基因包括载脂蛋白E、胆固醇24羟化酶(Cyp46)、酰基辅酶a:胆固醇-甾醇乙酰转移酶(ACAT)和胆固醇转运蛋白ABCA1。其他研究表明,在阿尔茨海默病的早期,胆固醇或其前体水平升高。最后,淀粉样前体蛋白加工的研究表明,胆固醇及其分解代谢物调节淀粉样前体蛋白的加工和Aβ的产生。这些证据表明,胆固醇代谢的遗传异常可能与AD的病理生理有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Cellular Biochemistry of Cholesterol and Statins: Insights into the Pathophysiology and Therapy of Alzheimer's Disease

The causes of late onset Alzheimer disease (AD) are poorly understood. Although β-amyloid (Aβ) is thought to play a critical role in the pathophysiology of AD, no genetic evidence directly ties Aβ to late onset AD. This suggests that the accumulation of Aβ and neurodegeneration associated with AD might result from an abnormality that indirectly affects Aβ production or accumulation. Increasing evidence suggests that abnormalities in the metabolism of cholesterol and related molecules, such as cholseterol esters and 24(S) hydroxycholesterol might contribute to the pathophysiology of late onset AD by increasing production of Aβ. 24(S) Hydroxycholesterol is a member of a family of oxidized cholesterol catabolites, termed oxysterols, which function to regulate export of cholesterol from the cell and transcription of genes related to cholesterol metabolism. Cholesterol esters are cholesterol derivatives used for cholesterol storage. Levels of 24(S) hydroxycholesterol increase with AD. Polymorphisms in several different genes important for cholesterol physiology are associated with an increased load or level of Aβ in AD. These genes include apolipoprotein E, cholesterol 24 hydroxylase (Cyp46), acyl-CoA:choles-terol acetyltransferase (ACAT), and the cholesterol transporter ABCA1. Other studies show that levels of cholesterol, or its precursors, are elevated in subjects early in the course of AD. Finally, studies of the processing of amyloid precursor protein show that cholesterol and its catabolites modulate amyloid precursor protein processing and Aβ production. These lines of evidence raise the possibility that genetic abnormalities in cholesterol metabolism might contribute to the pathophysiology of AD.

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