Effects of Statins on AD beyond Cholesterol and Amyloid

他汀类药物对 AD 的影响超越胆固醇和淀粉样蛋白

• 批准号: 6906706
• 负责人: LING LI
• 金额: $ 17.86万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6906706
• 关键词: Alzheimer' s disease; amyloid proteins; antihypercholesterolemic agent; behavior test; behavioral /social science research tag; disease /disorder model; drug screening /evaluation; genetically modified animals; hypercholesterolemia; laboratory mouse; memory; mental disorder chemotherapy; neuritic plaques; neuroprotectants; nonhuman therapy evaluation; pathologic process; pharmacology; psychological aspect of aging; simvastatin

DESCRIPTION (provided by applicant): The long-term goal of this project is to elucidate the mechanisms by which statins modify the risk of Alzheimer disease (AD). Statins are a class of cholesterol-lowering drugs that have been used successfully to prevent cardiovascular diseases. Recently, retrospective studies have shown an apparent reduction of risk for Alzheimer's disease in people receiving statins but not other classes of cholesterol-lowering drugs, suggesting protective effects of statins beyond cholesterol lowering. The powerful cholesterol-lowering effect of statins, however, has made it difficult to distinguish between the cholesterol and non-cholesterol effects of statins, as both mechanisms may affect the same pathogenic mechanisms. The protective effect of statins on Alzheimer's disease has been attributed to their ability to modulate the processing of amyloid-beta precursor protein leading to a decreased production of amyloid-p protein. In a preliminary study using a mouse model of Alzheimer's disease, however, a commonly used statin drug (simvastatin) enhances learning and memory independent of amyloid reduction. Therefore, the working hypothesis of this proposal is that statins modulate AD-related behavior and pathology beyond cholesterol lowering and amyloid reduction. This hypothesis will be tested by two Specific Aims: 1) to determine the efficacy of statins (simvastatin and pravastatin) and a non-statin cholesterol-lowering drug (ezetimibe) in modulating AD-type behavior and pathology in a mouse model of Alzheimer's disease. Simvastatin and pravastatin are chosen to represent the extremes of the lipophilicity spectrum of statins. Ezetimibe, a newly approved drug, is a potent, selective cholesterol absorption inhibitor. Because ezetimibe lowers plasma cholesterol but through a completely different mechanism from that of statins, it is an ideal drug for comparison with statins; 2) to determine if statins ameliorate AD-type behavior and pathology in a newly developed AD mouse model where it has no cholesterol-lowering effects. In this model, human-like hypercholesterolemia induced by the low-density lipoprotein receptor deficiency cannot be normalized by statin treatment. Therefore, using this unique mouse model, cholesterol-independent effects of statins on AD-type behavior and pathology will be distinguished from their cholesterol-lowering effects. Results of this study will help to dissect the pleiotropic effects of statins on Alzheimer's disease. They will also provide a starting point for future studies on elucidating the cellular and molecular mechanisms by which statins exert their neurobiological effects so that novel therapies may be developed to fight against Alzheimer's disease.

描述（由申请人提供）：该项目的长期目标是阐明他汀类药物改变阿尔茨海默氏病（AD）的风险的机制。他汀类药物是一类降低胆固醇的药物，已成功用于预防心血管疾病。最近，回顾性研究表明，接受他汀类药物的人，但没有其他类型的降低胆固醇的药物，明显降低了阿尔茨海默氏病的风险，这表明超出胆固醇以外的汀类药物的保护作用。然而，他汀类药物的强大降低胆固醇的作用使他很难区分他汀类药物的胆固醇和非胆固醇作用，因为这两种机制都可能影响相同的致病机制。他汀类药物对阿尔茨海默氏病的保护作用归因于它们调节淀粉样蛋白β前体蛋白的加工能力，从而导致淀粉样蛋白P蛋白的产生降低。然而，在使用阿尔茨海默氏病小鼠模型的初步研究中，一种常用的他汀类药物（Simvastatin）可以增强学习和记忆，而与淀粉样蛋白还原无关。因此，该提议的工作假设是他汀类药物调节了降低胆固醇和淀粉样蛋白还原以外与广告相关的行为和病理。该假设将通过两个具体目的来检验：1）确定他汀类药物（辛伐他汀和pravastatin）的疗效和一种非状态蛋白胆固醇药物（Ezetimibe）在调节阿尔茨海默氏病小鼠模型中的AD-type行为和病理学对AD-TYPE行为和病理学中的疗效。选择辛伐他汀和pravastatin来代表他汀类药物的亲脂性光谱的极端。 Ezetimibe是一种新批准的药物，是一种有效的选择性胆固醇抑制剂。由于ezetimibe降低了血浆胆固醇，但通过与他汀类药物完全不同的机制，它是与他汀类药物进行比较的理想药物。 2）确定他汀类药物在新开发的AD小鼠模型中是否可以改善AD型行为和病理，在该模型中没有降低胆固醇的作用。在此模型中，低密度脂蛋白受体缺乏症诱导的人类高胆固醇血症不能通过他汀类药物治疗进行标准化。因此，使用这种独特的小鼠模型，他汀类药物对AD型行为和病理学的胆固醇无关的作用将与降低胆固醇的作用区分开。这项研究的结果将有助于剖析他汀类药物对阿尔茨海默氏病的多效作用。他们还将为未来的研究提供一个起点，以阐明他汀类药物发挥神经生物学作用的细胞和分子机制，从而可以开发出新的疗法来对抗阿尔茨海默氏病。