Mechanism of Actions of Multitasking of Statins in AD

他汀类药物多任务治疗 AD 的作用机制

• 批准号: 7116501
• 负责人: Inderjit Singh
• 金额: $ 14.26万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116501
• 关键词: Alzheimer' s disease; amyloid proteins; antihypercholesterolemic agent; antiinflammatory agents; astrocytes; biological signal transduction; brain disorder chemotherapy; chemoprevention; cholesterol; drug screening /evaluation; genetically modified animals; immunomodulators; isoprenoid; laboratory mouse; lovastatin; mevalonate; microglia; myelinopathy; naphthalenes; neuropharmacology; neurotoxicology; nonhuman therapy evaluation; oligodendroglia; pharmacokinetics; tissue /cell culture

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.

阿尔茨海默病 (AD) 的特点是 β 淀粉样蛋白 (Aβ) 过度积累，这是 APR 交替加工的结果，Aβ 诱导的斑块和相关的神经炎症会促进 AD 病理。高胆固醇血症是 AD 危险因素的记录以及使用他汀类药物的患者中 AD 患病率的降低以及使用他汀类药物治疗的 AD 小鼠中 Aβ 负荷的减少支持甲羟戊酸途径的代谢物（胆固醇和类异戊二烯）在 AD 病理学中的作用。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，目前正在测试这种药物作为神经炎症/神经退行性疾病的可能治疗剂，然而，人们对这些药物在神经炎症疾病中的作用机制知之甚少。因此，所提出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 使用 AD 细胞培养模型（具体目标 1 和 2）研究他汀类药物在 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，及其在动物模型中降低胆固醇对 Aβ 积累和炎症性疾病负担的功效AD (TgCRNDS)（具体目标 3）。了解他汀类药物的抗淀粉样蛋白生成和免疫调节特性应有助于确定其作为一种新型非侵入性预防疗法的效用，用于在 AD 治疗中同时减少淀粉样蛋白负荷和炎症。