Sidera Christina, Parsons Richard, Austen Brian
Neurodegeneration Unit, Dept. Basic Medical Sciences, St George's Hospital Medical School, Cranmer Terrace, SW17 ORE, London, UK.
J Neurol Sci. 2005 Mar 15;229-230:269-73. doi: 10.1016/j.jns.2004.11.044. Epub 2004 Dec 21.
Epidemiologists have found a decreased risk of developing Alzheimer's disease (AD) in people taking statins (cholesterol biosynthesis inhibitors). We have reported previously that, in cell culture, lovastatin decreases the output of beta-amyloid, a peptide that is toxic to neurones, and is reputably the prime cause of neurodegeneration seen in AD. This report probes the mechanism of statin protection further by finding out how the protease beta-secretase, that releases beta-amyloid from its precursor protein, behaves under changed cholesterol levels induced by statins. We found that, with high cellular cholesterol levels, there is a decrease in glycosylation of mature oligosaccharides in beta-secretase, whereas in the presence of lovastatin, glycosylation progresses further. Moreover, lovastatin does not inhibit beta-secretase in vitro. Thus, the cholesterol and statin effects are due to changes in cellular targeting induced by changed cholesterol gradients. Some of these changes are mimicked by the action of U18666A, a cholesterol-transport inhibitor that produces a defect in cells seen in patients with Neimann Pick's disorder.
流行病学家发现，服用他汀类药物（胆固醇生物合成抑制剂）的人群患阿尔茨海默病（AD）的风险降低。我们之前曾报道，在细胞培养中，洛伐他汀可降低β-淀粉样蛋白的产量，β-淀粉样蛋白是一种对神经元有毒性的肽，被认为是AD中神经退行性变的主要原因。本报告通过研究蛋白酶β-分泌酶（从其前体蛋白释放β-淀粉样蛋白）在他汀类药物诱导的胆固醇水平变化下的行为，进一步探究他汀类药物的保护机制。我们发现，在细胞胆固醇水平较高时，β-分泌酶中成熟寡糖的糖基化减少，而在洛伐他汀存在的情况下，糖基化进一步进行。此外，洛伐他汀在体外不抑制β-分泌酶。因此，胆固醇和他汀类药物的作用是由于胆固醇梯度变化引起的细胞靶向改变。其中一些变化可被U18666A的作用模拟，U18666A是一种胆固醇转运抑制剂，会在患有尼曼-匹克病的患者细胞中产生缺陷。
