Cholesterol in Alzheimer's disease: unresolved questions.
Cholesterol in Alzheimer's disease: unresolved questions.
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DOI：
10.2174/156720509787313899
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发表时间：
2009-01
影响因子：
2.1
通讯作者：
M. Stefani;G. Liguri
中科院分区：
文献类型：
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作者：
M. Stefani;G. Liguri
胆固醇在神经退行性变中作为易感因子或保护剂的作用，以及更普遍地，在淀粉样蛋白诱导的细胞毒性中的作用仍然存在争议。关于高胆固醇血症-AD风险关系的流行病学研究和一些表明他汀类药物治疗有益作用的报告表明胆固醇是AD的易感因素。ApoE 4基因型作为AD的普遍遗传风险因素以及ApoE作为大脑中主要胆固醇载体的功能也构成了胆固醇负荷与AD风险密切相关的基础。最后，细胞生物学证据支持脂筏胆固醇在APP的β-和γ-分泌酶裂解的调节中的关键参与，改变了Abeta的产生。然而，循环和脑胆固醇之间几乎不存在交换，后者由内源性合成产生。此外，越来越多的证据支持这样的观点，即在大多数情况下，淀粉样蛋白的细胞毒性是由细胞膜上的寡聚体募集引起的，伴随着膜完整性的丧失、Ca（2+）进入细胞、氧化应激和细胞凋亡。在这种情况下，增加膜胆固醇似乎是保护不利的聚集体结合到膜。最近的研究结果还表明，细胞胆固醇的减少有利于BACE 1和APP在非筏膜结构域中的共定位，并阻碍纤溶酶（一种A β降解酶）的产生。最后，最近对参与胆固醇生物合成的Seladin-1的研究表明，膜胆固醇的调节影响Abeta产生和细胞对Abeta寡聚体毒性的抗性。这些数据证实了以前的研究结果，表明老年人和AD大脑中的胆固醇/磷脂比降低。这篇综述的目的是批判性地讨论近年来在这一领域报道的一些主要结果，这些结果支持胆固醇作为AD的易感因素或保护剂的作用。
The role of cholesterol as a susceptibility factor or a protective agent in neurodegeneration and, more generally, in amyloid-induced cytotoxicity is still controversial. Epidemiological studies on the hypercholesterolemia-AD risk relation and some reports indicating a beneficial effect of statin therapy suggest cholesterol as a susceptibility factor in AD. The ApoE4 genotype as a prevalent genetic risk factor for AD and the function of ApoE as main cholesterol carrier in the brain also underlie a close cholesterol load-AD risk relation. Finally, cell biology evidences support a critical involvement of lipid raft cholesterol in the modulation of beta- and gamma-secretase cleavage of APP with altered Abeta production. However, little exchange does exist between circulating and brain cholesterol, the latter arising from endogenous synthesis. In addition, increasing evidence supports the idea that amyloid cytotoxicity in most cases is initiated by oligomer recruitment at the cell membrane with loss of membrane integrity, Ca(2+) ingress into the cell, oxidative stress and apoptosis. In such a scenario, increased membrane cholesterol seems to be protective by disfavouring aggregate binding to the membrane. Recent findings also indicate that a reduction of cellular cholesterol favours co-localization of BACE1 and APP in non-raft membrane domains and hinders generation of plasmin, an Abeta-degrading enzyme. Finally, recent researches on Seladin-1, involved in cholesterol biosynthesis, show that modulation of membrane cholesterol affects Abeta generation and cell resistance against Abeta oligomer toxicity. These data confirm previous findings indicating a reduction of the cholesterol/phospholipid ratio in aged and AD brains. The aim of this review is to critically discuss some of the main results reported in the recent years in this field supporting a role of cholesterol either as a susceptibility factor or as a protective agent in AD.