Anaesthetics, Pain Medicine and Intensive Care, Division of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, UK.
J Alzheimers Dis. 2011;27(1):1-10. doi: 10.3233/JAD-2011-110524.
Alzheimer's disease (AD) is a progressive neurodegenerative disease commonly seen in the elderly and is characterized by progressive cognitive and physical decline. Current understanding of AD pathogenesis revolves around amyloid-β peptide (Aβ), a product of the sequential proteolytic cleavage of the transmembrane amyloid-β protein precursor (AβPP) by β- and γ-secretase, enzymes found predominantly in the cholesterol rich micro domains of the cell membrane. Several risk factors for AD are associated with cholesterol metabolism, including dyslipidaemia, coronary artery and cerebrovascular disease. Statins are widely prescribed for their cholesterol lowering ability and show a favorable side effect profile overall. By competitive inhibition of hydroxymethyl co-enzyme A-reductase, statins reduce the production of cholesterol and isoprenoid intermediates including geranylgeranyl and farnesyl pyrophosphate. These isoprenoids modify recently translated proteins such as small GTPase molecules that are essential in numerous cell-signaling pathways, including vesicular trafficking and inflammation. In experimental models of AD, statins reduce the production of Aβ by disrupting secretase enzyme function and by reducing neuroinflammation. Furthermore, epidemiological studies suggest that statins may reduce the incidence of AD. Consequently, statins, secondary of their anti-hypercholesterolaemic, plieotropic and anti-inflammatory effects, are being investigated for a potential therapeutic role. This review will discuss evidence for the role of statins in the treatment and prevention of AD neurodegeneration.
阿尔茨海默病（AD）是一种常见于老年人的进行性神经退行性疾病，其特征是进行性认知和身体衰退。目前对 AD 发病机制的理解主要围绕淀粉样β肽（Aβ）展开，Aβ是跨膜淀粉样β蛋白前体（AβPP）经β-和γ-分泌酶顺序蛋白水解切割的产物，这些酶主要存在于细胞膜的胆固醇丰富的微域中。AD 的几个危险因素与胆固醇代谢有关，包括血脂异常、冠状动脉和脑血管疾病。他汀类药物因其降低胆固醇的能力而被广泛开处方，并具有总体有利的副作用谱。通过竞争性抑制羟甲基戊二酰基辅酶 A 还原酶，他汀类药物减少胆固醇和异戊烯基中间产物（包括香叶基和法尼基焦磷酸）的产生。这些异戊烯基修饰最近翻译的蛋白质，如在包括囊泡运输和炎症在内的许多细胞信号通路中必不可少的小 GTPase 分子。在 AD 的实验模型中，他汀类药物通过破坏分泌酶酶的功能和减少神经炎症来减少 Aβ的产生。此外，流行病学研究表明他汀类药物可能降低 AD 的发病率。因此，他汀类药物因其抗高胆固醇血症、多效性和抗炎作用而被用于治疗 AD 神经退行性变的潜在治疗作用的研究。本综述将讨论他汀类药物在 AD 神经退行性变治疗和预防中的作用证据。
