Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer β-amyloid peptide in vitro and in patients
Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer β-amyloid peptide in vitro and in patients
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DOI：
10.2741/buxbaum
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发表时间：
2002-04-01
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影响因子：
--
通讯作者：
Friedhoff, LT
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文献类型：
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作者：
Buxbaum, JD;Cullen, EI;Friedhoff, LT
流行病学研究表明，高胆固醇血症是阿尔茨海默病（AD）的危险因素。由于β-淀粉样肽（Abeta）在脑中的产生和积累似乎对AD的起始和进展具有重要意义，因此胆固醇水平可能调节Abeta的形成和/或清除。为了测试改变胆固醇对Abeta形成的影响，我们将细胞与或不与洛伐他汀酸（HMG-CoA还原酶抑制剂洛伐他汀的活性代谢物）一起孵育，并测量在每种条件下由其前体形成的Abeta的分数。我们观察到，用洛伐他汀酸处理导致形成的A β水平显著降低。在0.05-5 μ M的浓度下观察到这种效果，在该浓度范围内该化合物有效抑制HMG-CoA还原酶。为了检查洛伐他汀对体内A β的影响，在一项双盲、随机研究中，对低密度脂蛋白胆固醇升高的人类受试者给予10-60 mg洛伐他汀控释制剂或匹配的安慰剂，每日一次。在治疗前和治疗后最多3个月测量血清Abeta浓度。血清A β浓度较基线的平均和中位变化显示显著（小于或等于0.0348）剂量依赖性降低。40和60 mg剂量组与安慰剂组之间的差异具有统计学意义（Dunnett's p
Epidemiological studies demonstrate that hypercholesterolemia is a risk factor for Alzheimer's disease (AD). As the generation and accumulation of the beta-amyloid peptide (Abeta) in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels regulate Abeta formation and/or clearance. To test the effects of altering cholesterol on Abeta formation, we incubated cells with or without lovastatin acid, the active metabolite of the HMG-CoA reductase inhibitor lovastatin, and measured the fraction of Abeta formed from its precursor under each condition. We observed that treatment with lovastatin acid led to a profound decrease in the levels of Abeta formed. This effect was observed at concentrations of 0.05-5 muM, ranges where this compound is effective at inhibiting HMG-CoA reductase. To examine the effects of lovastatin on Abeta in vivo, human subjects who had elevated low-density lipoprotein cholesterol were treated during a double-blind, randomized study with 10-60-mg once-daily doses of a controlled-release formulation of lovastatin, or matching placebo. Serum Abeta concentrations were measured before and after up to 3 months of treatment. Mean and median changes from baseline in serum Abeta concentrations showed a significant (pless than or equal to0.0348), dose-dependent decrease. Differences between the 40- and 60-mg dose groups and placebo were statistically significant (Dunnett's p