Vega Gloria Lena, Weiner Myron F
The Nutrition and Metabolism Laboratory, Metabolic Unit, Veterans Affairs Medical Center, Dallas, TX 75390, USA.
J Mol Neurosci. 2007 Sep;33(1):51-5. doi: 10.1007/s12031-007-0040-5.
A number of epidemiologic studies suggest an association between plasma total cholesterol and risk for Alzheimer's disease (AD). Additionally, it has been suggested that treatment with statins, drugs that block cholesterol biosynthesis, lower the incidence and prevalence of AD and of vascular dementia. This review provides an overview of cholesterol transport within the central nervous system and the impact of statins on brain cholesterol metabolism in subjects with AD. Brain cholesterol is converted to 24-S-hydroxycholesterol, a reaction catalyzed by CYP46. The oxysterol traverses the blood-brain barrier and is transported to the liver by plasma lipoproteins. The levels of 24-S-hydroxy-cholesterol are a reflection of brain cholesterol turnover. Subjects with AD reportedly have high levels of the oxysterol possibly reflecting neuronal death with release of cell membrane cholesterol. We show gender dimorphism in plasma levels of 24-S-hydroxycholesterol in subjects with AD and significant reductions in plasma levels of the oxysterol during treatment with standard doses of statins (lovastatin, simvastatin, and pravastatin). Polymorphisms of apolipoprotein E and CYP46 do not influence the effect of statins on plasma levels of 24-S-hydroxycholesterol. There were no untoward effects of the standard doses of statin for the duration of treatment. Statins are currently in trial to determine their effect on the course of AD.
多项流行病学研究表明，血浆总胆固醇与阿尔茨海默病（AD）风险之间存在关联。此外，有研究表明，使用他汀类药物（即阻断胆固醇生物合成的药物）进行治疗可降低AD和血管性痴呆的发病率及患病率。本综述概述了中枢神经系统内的胆固醇转运以及他汀类药物对AD患者脑胆固醇代谢的影响。脑胆固醇在细胞色素P450 46（CYP46）催化下转化为24S-羟基胆固醇。这种氧化甾醇穿过血脑屏障，并通过血浆脂蛋白转运至肝脏。24S-羟基胆固醇的水平反映了脑胆固醇的更新情况。据报道，AD患者的这种氧化甾醇水平较高，这可能反映了神经元死亡并伴有细胞膜胆固醇的释放。我们发现，AD患者血浆中24S-羟基胆固醇水平存在性别差异，且在使用标准剂量他汀类药物（洛伐他汀、辛伐他汀和普伐他汀）治疗期间，该氧化甾醇的血浆水平显著降低。载脂蛋白E和CYP46的多态性不影响他汀类药物对24S-羟基胆固醇血浆水平的作用。在治疗期间，标准剂量的他汀类药物未产生不良影响。目前正在对他汀类药物进行试验，以确定其对AD病程的影响。
