The Gertrude H. Sergievsky, the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and the Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Curr Atheroscler Rep. 2013 Mar;15(3):307. doi: 10.1007/s11883-012-0307-3.
Whether cholesterol is implicated in the pathogenesis of Alzheimer's disease (AD) is still controversial. Several studies that explored the association between lipids and/or lipid-lowering treatment and AD indicate a harmful effect of dyslipidemia on AD risk. The findings are supported by genetic linkage and association studies that have clearly identified several genes involved in cholesterol metabolism or transport as AD susceptibility genes, including apolipoprotein E (APOE), apolipoprotein J (APOJ, CLU), ATP-binding cassette subfamily A member 7(ABCA7), and sortilin-related receptor (SORL1). Functional cell biology studies further support a critical involvement of lipid raft cholesterol in the modulation of Aβ precursor protein processing by β-secretase and γ-secretase resulting in altered Aβ production. However, conflicting evidence comes from epidemiological studies showing no or controversial association between dyslipidemia and AD risk, randomized clinical trials observing no beneficial effect of statin therapy, and cell biology studies suggesting that there is little exchange between circulating and brain cholesterol, that increased membrane cholesterol level is protective by inhibiting loss of membrane integrity through amyloid cytotoxicity, and that cellular cholesterol inhibits colocalization of β-secretase 1 and Aβ precursor protein in nonraft membrane domains, thereby increasing generation of plasmin, an Aβ-degrading enzyme. The aim of this article is to provide a comprehensive review of the findings of epidemiological, genetic, and cell biology studies aiming to elucidate the role of cholesterol in the pathogenesis of AD.
胆固醇是否与阿尔茨海默病（AD）的发病机制有关仍存在争议。一些探讨脂质和/或降脂治疗与 AD 之间关系的研究表明，血脂异常对 AD 风险有不良影响。遗传连锁和关联研究的结果支持了这一观点，这些研究明确鉴定了几种参与胆固醇代谢或转运的基因是 AD 易感基因，包括载脂蛋白 E（APOE）、载脂蛋白 J（APOJ、CLU）、ATP 结合盒亚家族 A 成员 7（ABCA7）和分选相关受体（SORL1）。功能细胞生物学研究进一步支持脂质筏胆固醇在调节β-分泌酶和γ-分泌酶切割 Aβ 前体蛋白从而改变 Aβ 产生方面的关键作用。然而，来自流行病学研究的矛盾证据表明，血脂异常与 AD 风险之间没有或存在争议的关联，随机临床试验观察到他汀类药物治疗没有益处，细胞生物学研究表明，循环胆固醇与大脑胆固醇之间几乎没有交换，增加膜胆固醇水平通过抑制膜完整性丧失来保护细胞免受淀粉样蛋白细胞毒性，并且细胞胆固醇抑制β-分泌酶 1 和 Aβ 前体蛋白在非筏膜域中的共定位，从而增加了 Aβ 降解酶纤溶酶的生成。本文的目的是提供对流行病学、遗传学和细胞生物学研究结果的综合回顾，旨在阐明胆固醇在 AD 发病机制中的作用。
