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，预防心脏病。有趣的是，虽然回顾性研究显示服用他汀类药物的人患阿尔茨海默病的几率降低，但前瞻性研究报告的结果却喜忧参半。因此，临床数据的差异促使新的研究来确定他汀类药物影响认知功能的基本机制。在美国有超过500万人患有阿尔茨海默病，并且没有令人满意的治疗方法来减缓或逆转这种疾病，这强调了澄清他汀类药物治疗阿尔茨海默病的益处的必要性。正在进行的临床试验进一步强调了这一点，例如降胆固醇剂（辛伐他汀）减缓AD进展（CLASP） （ClinicalTrials.gov标识号：NCT00053599）。虽然他汀类药物对AD的有益作用得到了他汀类药物降低胆固醇水平和减少淀粉样蛋白（AB）产生的研究的支持，但新出现的证据表明，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在不影响脑胆固醇和AB水平的情况下挽救了AD小鼠模型的学习和记忆缺陷，但增加了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)他汀类药物通过抵消ab诱导的毒性和/或直接调节突触可塑性来发挥促突触/促认知作用；B)他汀类药物的保护作用是由多种途径介导的，其中大多数途径与胆固醇无关；c)他汀类药物降低AB水平的功效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；d)直接影响神经元可能需要他汀类药物进入大脑。这些假设将通过行为学、电生理学和生物化学方法在体内和体外的三个特定目的进行验证：1)确定不同他汀类药物在AD小鼠模型中调节AD样行为和病理的功效。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）渗透性将被评估。2)观察他汀类药物对小鼠海马突触可塑性的影响。电生理学方法将用于研究他汀类药物对海马突触可塑性的影响。3)阐明他汀类药物发挥保护作用的细胞和分子机制。根据Aim 1和Aim 2的研究结果，原代神经元培养将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阿尔茨海默病的机制提供重要的见解，从而开发出新的治疗方法来对抗阿尔茨海默病。公共卫生相关性：新出现的证据表明，他汀类药物是一种降低胆固醇水平和预防心血管疾病的有效药物，可预防阿尔茨海默病（AD）的发展，AD是老年人痴呆症的主要原因。本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。这个项目的结果可能会带来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.