Mechanism of Actions of Multitasking of Statins in AD

阿尔茨海默病(AD)的特征是由于APR的交替处理而导致β淀粉样蛋白(Aβ)过度聚集，Aβ诱导的斑块和相关的神经炎症促进AD的病理。高胆固醇血症是AD的危险因素，使用他汀类药物的患者中AD患病率降低，使用他汀类药物治疗的AD小鼠的Aβ负荷减少，这支持甲氧戊酸途径的代谢物(胆固醇和异戊二烯)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，该药物目前正在作为一种可能的神经炎性/神经退行性疾病的治疗剂进行测试，但对这些药物在神经炎性疾病中的作用机制知之甚少。因此，本研究旨在了解甲氧戊酸途径的代谢物在多任务活动中的作用机制。 他汀类药物在Aβ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症性疾病中的作用通过使用AD细胞培养模型(特异性目标1和2)以及它们在AD动物模型(TgCRNDS)(特异性目标3)中降低胆固醇对Aβ蓄积和炎症性疾病的负担(特异性目标3)来实现。了解他汀类药物的抗淀粉样蛋白生成和免疫调节特性将有助于建立其作为一种新的非侵入性预防疗法的用途，在AD的治疗中同时减少淀粉样蛋白负担和炎症。

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.