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病（AD）风险的机制。他汀类药物是一类降胆固醇药物，已成功用于预防心血管疾病。最近，回顾性研究表明，接受他汀类药物但接受其他类别降胆固醇药物的人患阿尔茨海默病的风险明显降低，这表明他汀类药物除了降低胆固醇之外还有保护作用。然而，他汀类药物强大的降胆固醇作用使得很难区分他汀类药物的胆固醇作用和非胆固醇作用，因为这两种机制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能够调节淀粉样蛋白-β前体蛋白的加工，从而导致淀粉样蛋白-β蛋白的产生减少。然而，在使用阿尔茨海默病小鼠模型的初步研究中，常用的他汀类药物（辛伐他汀）可以增强学习和记忆，而与淀粉样蛋白的减少无关。因此，该提案的工作假设是，他汀类药物除了降低胆固醇和减少淀粉样蛋白之外，还可以调节 AD 相关的行为和病理。该假设将通过两个具体目标进行检验：1) 确定他汀类药物（辛伐他汀和普伐他汀）和非他汀类降胆固醇药物（依折麦布）在调节阿尔茨海默病小鼠模型中 AD 型行为和病理学方面的功效。选择辛伐他汀和普伐他汀来代表他汀类药物亲脂性谱的极端情况。依折麦布是一种新批准的药物，是一种有效的选择性胆固醇吸收抑制剂。由于依折麦布降低血浆胆固醇的作用机制与他汀类药物完全不同，因此是与他汀类药物比较的理想药物； 2) 确定他汀类药物是否可以改善新开发的 AD 小鼠模型中的 AD 型行为和病理学，而该模型没有降低胆固醇的作用。在该模型中，由低密度脂蛋白受体缺陷引起的类人高胆固醇血症不能通过他汀类药物治疗恢复正常。因此，使用这种独特的小鼠模型，他汀类药物对 AD 型行为和病理的非胆固醇依赖性作用将与其降低胆固醇的作用区分开来。这项研究的结果将有助于剖析他汀类药物对阿尔茨海默病的多效作用。他们还将为未来的研究提供一个起点，阐明他汀类药物发挥其神经生物学作用的细胞和分子机制，以便开发新的疗法来对抗阿尔茨海默病。