Mechanism of Actions of Multitasking of Statins in AD

阿尔茨海默病（AD）的特征在于由于APR的交替加工而导致的β淀粉样蛋白（A β）的过度积累，并且A β诱导的斑块和相关的神经炎症促进AD病理学。高胆固醇血症是AD的风险因素，在使用他汀类药物的患者中AD患病率降低，以及在接受他汀类药物治疗的AD小鼠中A β负荷降低，这些证据支持了甲羟戊酸途径的代谢产物（胆固醇和类异戊二烯）在AD病理生物学中的作用。我们实验室的研究还报告说，除了调节胆固醇水平外，他汀类药物还具有 抗炎特性。基于他汀类药物的抗炎特性，这种药物现在正在测试作为神经炎症/神经退行性疾病的可能治疗剂，然而，对这些药物在神经炎症性疾病中的作用机制知之甚少。因此，拟定的研究旨在了解甲羟戊酸途径代谢物在多任务活动中的作用机制， 通过使用AD细胞培养模型（特定目的1和2），研究他汀类药物在A β介导的少突胶质细胞毒性和星形胶质细胞/小胶质细胞诱导的炎性疾病中的作用，以及在AD动物模型（TgCRNDS）中降低胆固醇对A β蓄积和炎性疾病负担的作用（特定目的3）。了解他汀类药物的抗淀粉样蛋白生成和免疫调节特性有助于建立其作为一种新型非侵入性预防性治疗的效用，以减少淀粉样蛋白负荷和炎症同时在AD的管理。

Alzheimer's disease (AD) is characterized by excessive accumulation of beta amyloid (A beta), as a consequence of alternate processing of APR, and A beta-induced plaque and associated neuroinflammation promote AD pathology. Documentation of hypercholesterolemia as a risk factor for AD and reduced prevalence of AD among patients using statins and reduced load of A beta in AD mice treated with statins support of a role of metabolites (cholesterol and isoprenoids) of the mevalonate pathway in the pathobiology of AD. Studies from our laboratory have also reported that in addition to regulation of cholesterol levels statins also have anti-inflammatory properties. Based on the anti-inflammatory properties of statins, this drug is now being tested as a possible therapeutic agent for neuroinflammatory/neurodegenerative disease, however, very little is known about the mechanism of action of these drugs in neuroinflammatory diseases. Therefore, the proposed studies are designed to understand the mechanism of action of metabolites of the mevalonate pathway in multitasking activities of statins in the A beta mediated oligodendrocyte toxicity and astrocyte/microglia induced inflammatory disease by using a cell culture model of AD (Specific Aims 1 and 2) and their efficacy in lowering cholesterol on the burden of A beta accumulation and inflammatory disease with an animal model of AD (TgCRNDS) (Specific Aim 3). Understanding anti-amyloidogenic and immunomodulatory properties of statins should help establish their utilitiy as a novel noninvasive prophylactic therapy for reducing amyloid burden and inflammation simultaneously in the management of AD.