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: 6989318
• 负责人: Inderjit Singh
• 金额: $ 14.6万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989318
• 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.

阿尔茨海默氏病（AD）的特征是β-淀粉样蛋白（β）的过度积累，由于APR的替代加工而导致β诱导的斑块和相关的神经炎症促进了AD病理学。在使用他汀类药物的患者中，高胆固醇血症作为AD患者的AD和AD患病率降低的危险因素的文献记录，并减少了用他汀类药物治疗的AD小鼠的β小鼠的负载，并在AD病原体病理生物学中用他汀类药物的支持（胆固醇和异戊酸）的作用（胆固醇和异磷酸酯）的作用。我们实验室的研究还报道说，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，该药物现在正在作为神经炎性/神经退行性疾病的可能治疗剂进行测试，但是，对于这些药物在神经炎症性疾病中的作用机理知之甚少。因此，拟议的研究旨在理解甲戊酸途径代谢物在多任务活动中的代谢物的作用机理。 Aβ介导的少突胶质细胞毒性和星形胶质细胞/小胶质细胞中的他汀类药物通过使用AD的细胞培养模型（特定目的1和2）诱导炎症性疾病，及其在降低胆固醇的功效下，降低胆固醇的负担，并具有beta积累和炎症性疾病的负担，并具有AD AD动物模型（TGCRNDS）（特定目标3）。理解他汀类药物的抗淀粉样生殖和免疫调节特性应有助于确立其功效，作为一种新型的无创预防治疗，以同时减少AD管理中的淀粉样蛋白负担和炎症。