Effects of Statins on AD beyond Cholesterol and Amyloid

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，服用他汀类药物的人患阿尔茨海默病的风险明显降低，而其他类型的降胆固醇药物则没有，这表明他汀类药物的保护作用不仅仅是降胆固醇。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和非胆固醇作用，因为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病的保护作用归因于其调节淀粉样蛋白- β前体蛋白加工的能力，导致淀粉样蛋白-p蛋白的产生减少。然而，在一项使用阿尔茨海默病小鼠模型的初步研究中，一种常用的他汀类药物（辛伐他汀）可以增强学习和记忆，而不依赖于淀粉样蛋白的减少。因此，这项提议的工作假设是他汀类药物调节ad相关的行为和病理，而不仅仅是降低胆固醇和减少淀粉样蛋白。这一假设将通过两个特定目的来验证：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（依泽替米贝）在阿尔茨海默病小鼠模型中调节ad型行为和病理的功效。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。Ezetimibe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。因为依折替米比降低血浆胆固醇的机制与他汀类药物完全不同，所以它是与他汀类药物比较的理想药物；2)在新开发的AD小鼠模型中，确定他汀类药物是否改善AD型行为和病理，而他汀类药物没有降胆固醇作用。在这个模型中，由低密度脂蛋白受体缺乏引起的类人高胆固醇血症不能通过他汀类药物治疗正常化。因此，使用这种独特的小鼠模型，他汀类药物对ad型行为和病理的胆固醇非依赖性作用将与其降胆固醇作用区分开来。本研究结果将有助于剖析他汀类药物对阿尔茨海默病的多效性作用。他们也将为未来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的研究提供一个起点，从而可能开发出新的治疗方法来对抗阿尔茨海默病。

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.