Protective Mechanisms of Statins in 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预防阿尔茨海默病(AD)的细胞和分子机制。他汀类药物是一类抑制胆固醇生物合成的药物。目前，超过3600万美国人正在服用他汀类药物来降低血浆胆固醇水平和预防心脏病。有趣的是，虽然回顾研究表明服用他汀类药物的患者AD患病率降低，但前瞻性研究报告的结果喜忧参半。因此，临床数据中的差异激发了新的研究，以确定他汀类药物影响认知功能的基本机制。美国有500多万人患有阿尔茨海默病，没有令人满意的治疗方法来减缓或逆转疾病，这突显了澄清他汀类药物治疗阿尔茨海默病的益处的迫切需要。正在进行的临床试验进一步强调了这一点，例如降胆固醇药物(辛伐他汀)以减缓AD进展(CLAP)(ClinicalTrials.gov识别码：NCT00053599)。虽然他汀类药物在AD中的有益作用得到了研究的支持，研究表明他汀类药物降低胆固醇水平和减少淀粉样β蛋白(AB)的产生，但越来越多的证据表明，他汀类药物的保护作用不仅仅是降低胆固醇和AB水平。最近，我们已经证明，辛伐他汀可以在不影响脑胆固醇和AB水平的情况下，挽救AD小鼠模型的学习和记忆缺陷，但增加与记忆形成和突触可塑性相关的信号分子的磷酸化。因此，我们的工作假设是：a)他汀类药物通过对抗AB诱导的毒性和/或直接调节突触可塑性而发挥突触/认知前效应；b)他汀类药物的保护作用由多个途径介导，其中大多数不依赖于胆固醇；c)他汀类药物降低AB水平的有效性取决于他汀类药物治疗开始时的疾病阶段以及他汀类药物的选择和剂量；以及d)直接的神经元效应可能需要他汀类药物进入大脑。这些假说将通过三个特定的目标进行验证，结合体内和体外的行为、电生理和生化方法：1)确定不同的他汀类药物在AD小鼠模型中调节AD样行为和病理的有效性。三种他汀类药物(辛伐他汀、阿托伐他汀和瑞舒伐他汀)具有不同的亲脂性和血脑屏障(BBB)通透性。2)观察他汀类药物对小鼠海马片突触可塑性的影响。电生理方法将被用来研究他汀类药物对海马区突触可塑性的影响。3)阐明他汀类药物发挥保护作用的细胞和分子机制。根据目标1和目标2的发现，原代神经元培养将被用于更详细的机制研究，以确定他汀类药物发挥作用的细胞和分子事件。这些研究的结果将为他汀类药物预防AD的机制提供重要的见解，从而可能开发新的治疗方法来对抗AD。公共卫生研究进展：新的证据表明，他汀类药物是一种有效的降低胆固醇水平和预防心血管疾病的药物，可以预防阿尔茨海默病(AD)的发展，阿尔茨海默病(AD)是导致老年人痴呆的主要原因。该项目旨在结合行为学、电生理学和生物化学方法来阐明他汀类药物发挥抗AD作用的细胞和分子机制。该项目的结果可能导致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 cellular and molecular mechanisms by which statins protect against Alzheimer's disease (AD). Statins are a class of drugs that inhibit the biosynthesis of cholesterol. Currently, over 36 million Americans are taking statins to lower plasma cholesterol levels and prevent heart disease. Interestingly, while retrospective studies show a reduced prevalence of AD in people taking statins, prospective studies report mixed results. Thus, the discrepancy in the clinical data motivates new investigations to define the basic mechanisms through which statins affect cognitive function. That over 5 million people in the US are living with AD and have no satisfactory treatment available to slow down or reverse the disease underscores the great need to clarify the benefits of statin treatment for AD. This is further emphasized by the ongoing clinical trials such as Cholesterol-Lowering Agent (simvastatin) to Slow Progression (CLASP) of AD (ClinicalTrials.gov identifier: NCT00053599). While the beneficial effects of statins in AD are supported by studies showing that statins lower cholesterol levels and decrease amyloid-beta (AB) production, emerging evidence suggests that the protective effects of statins are beyond lowering cholesterol and AB levels. Recently, we have shown that simvastatin rescues learning and memory deficits in a mouse model of AD without affecting brain cholesterol and AB levels but increases phosphorylation of signaling molecules pertinent to memory formation and synaptic plasticity. Therefore, our working hypotheses are: a) statins exert the pro-synaptic/pro-cognitive effects by counteracting AB-induced toxicity and/or by directly modulating synaptic plasticity; b) the protective effects of statins are mediated by multiple pathways, most of which are independent of cholesterol; c) the efficacy of statins in decreasing AB levels depends on the stage of the disease at the initiation of the statin treatment as well as the choice and dose of statins; and d) direct neuronal effects may require the access of statins to the brain. These hypotheses will be tested by three specific aims using a combination of behavioral, electrophysiological, and biochemical approaches in vivo and in vitro: 1) To determine the efficacy of different statins in modulating AD-like behavior and pathology in a mouse model of AD. Three statins (simvastatin, atorvastatin, and rosuvastatin) that have different lipophilicity and blood-brain barrier (BBB) permeability will be evaluated. 2) To investigate the effect of statin treatment on synaptic plasticity in mouse hippocampal slices. Electrophysiological approaches will be employed to study the effect of statins on hippocampal synaptic plasticity. 3) To elucidate the cellular and molecular mechanisms by which statins exert protective effects. Depending on the findings from Aim 1 and 2, primary neuronal cultures will be used for more detailed mechanistic studies to define the cellular and molecular events by which statins exert their effects. Results from these studies will provide significant insight into the mechanisms by which statins protect against AD so that novel therapies may be developed to combat AD. PUBLIC HEALTH RELEVENCE: Emerging evidence indicates that statins, an effective medication for lowering cholesterol levels and preventing cardiovascular disease, are protective against the development of Alzheimer's disease (AD), a leading cause of dementia in elderly people. This project is designed to use a combination of behavioral, electrophysiological, and biochemical approaches to elucidate the cellular and molecular mechanisms by which statins exert anti-AD effects. Results from this project may lead to novel therapies to combat AD.