Wollmer M Axel
Psychiatric University Clinics, University of Basel, 4025 Basel, Switzerland.
Biochim Biophys Acta. 2010 Aug;1801(8):762-73. doi: 10.1016/j.bbalip.2010.05.009. Epub 2010 May 24.
Experimental data show that cholesterol can modulate central processes in the pathogenesis of Alzheimer's disease (AD). The epidemiological link between elevated plasma cholesterol at midlife and increased risk for AD and the possibility that 3-hydroxy-3-methylglutaryl-coenzym A reductase inhibitors (statins) may be protective against AD support a role of cholesterol metabolism in AD and have rendered it a potential therapeutic target in the treatment and prevention of the disease. The strong association of AD and AD endophenotypes with the APOE gene provides a genetic link between AD and cholesterol metabolism, because the apolipoprotein E (ApoE) is the most prevalent cholesterol transport protein in the central nervous system. Against this background several other genes with a role in cholesterol metabolism have been investigated for association with AD. In this review a compilation of genes related to cholesterol based on the information of the AmiGo gene ontology database is matched with the AlzGene database of AD candidate genes. 56 out of 149 (37.6%) genes with a relation to cholesterol metabolism have been investigated for association with AD. Given that only 660 out of about 23,000 (2.9%) genes have been assessed in hypothesis-driven candidate gene studies on AD, the cholesterol metabolic pathway is strongly represented among these genes. Among 34 cholesterol-related genes for which association with AD has been described APOE, CH25H, CLU, LDLR, SORL1 outstand with positive meta-analyses. However, it is unclear, if their association with AD is mediated by cholesterol-related mechanisms or by more specific direct effects of the respective proteins on Abeta metabolism.
实验数据表明，胆固醇可调节阿尔茨海默病（AD）发病机制中的中枢过程。中年时血浆胆固醇升高与AD风险增加之间的流行病学关联，以及3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）可能对AD具有保护作用，这支持了胆固醇代谢在AD中的作用，并使其成为该疾病治疗和预防的潜在治疗靶点。AD及AD内表型与APOE基因的强关联提供了AD与胆固醇代谢之间的遗传联系，因为载脂蛋白E（ApoE）是中枢神经系统中最普遍的胆固醇转运蛋白。在此背景下，人们研究了其他几个在胆固醇代谢中起作用的基因与AD的关联。在本综述中，基于AmiGo基因本体数据库的信息，将与胆固醇相关的基因汇编与AD候选基因的AlzGene数据库进行了匹配。在149个与胆固醇代谢相关的基因中，有56个（37.6%）已被研究与AD的关联。鉴于在关于AD的假设驱动候选基因研究中，约23000个基因中只有660个（2.9%）被评估，胆固醇代谢途径在这些基因中得到了强烈体现。在已描述与AD相关的34个胆固醇相关基因中，APOE、CH25H、CLU、LDLR、SORL1在荟萃分析中表现突出。然而，尚不清楚它们与AD的关联是由胆固醇相关机制介导，还是由各自蛋白质对淀粉样β蛋白代谢的更具体直接作用介导。
