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。他汀类药物是一类已成功用于预防心血管疾病的降胆固醇药物。最近，回顾性研究表明，服用他汀类药物而不是其他类别的降胆固醇药物的人患阿尔茨海默病的风险明显降低，这表明他汀类药物的保护作用超出了降低胆固醇的范围。然而，他汀类药物强大的降胆固醇作用使得区分他汀类药物的胆固醇和非胆固醇作用变得困难，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病的保护作用归因于它们调节淀粉样β前体蛋白的处理能力，导致淀粉样β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，而不是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除了降低胆固醇和淀粉样蛋白减少外，还调节与AD相关的行为和病理。这一假说将通过两个特定的目标进行验证：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(依折麦布)在调节阿尔茨海默病小鼠模型中的AD类型行为和病理方面的有效性。辛伐他汀和普伐他汀被选为代表他汀类药物亲脂性光谱的极端。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ezetimibe可降低血浆胆固醇，但机制与他汀类药物完全不同，因此它是与他汀类药物进行比较的理想药物；2)为了确定他汀类药物是否改善了一种新开发的AD小鼠模型的AD类型的行为和病理，在这种模型中，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陷引起的类人型高胆固醇血症不能通过他汀类药物治疗而正常化。因此，利用这一独特的小鼠模型，他汀类药物对AD类型行为和病理的胆固醇非依赖性作用将与它们的降胆固醇作用区分开来。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性作用。它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，从而可能开发出对抗阿尔茨海默病的新疗法。

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.