Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T
Department of Neurology, Clinic Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany.
Proc Natl Acad Sci U S A. 2001 May 8;98(10):5856-61. doi: 10.1073/pnas.081620098. Epub 2001 Apr 10.
Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated Abeta42 levels and the varepsilon4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of Abeta42 and Abeta40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral Abeta42 and Abeta40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of Abeta42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.
近期的流行病学研究表明，使用降胆固醇他汀类药物治疗的患者中，阿尔茨海默病的发病率大幅降低。此外，β淀粉样蛋白42（Aβ42）水平升高以及脂质载体载脂蛋白E的ε4等位基因被视为散发性和家族性阿尔茨海默病的危险因素。在此，我们证明，广泛使用的降胆固醇药物辛伐他汀和洛伐他汀可降低海马神经元和混合皮质神经元原代培养物中细胞内和细胞外的Aβ42和Aβ40肽水平。同样，用高剂量辛伐他汀治疗的豚鼠脑脊液和脑匀浆中的脑Aβ42和Aβ40水平也出现了显著且可逆的降低。这些结果表明，脂质在阿尔茨海默病的发展过程中起着重要作用。Aβ42水平降低可能为他汀类药物治疗患者中观察到的痴呆发病率降低提供了机制，并可能为治疗干预开辟途径。
