Protective Mechanisms of Statins in Alzheimer's Disease

他汀类药物对阿尔茨海默病的保护机​​制

• 批准号: 7438967
• 负责人: LING LI
• 金额: $ 29.73万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7438967
• 关键词: Admixture; Affect; Age; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Behavior; Behavioral; Biochemical; Blood - brain barrier anatomy; Brain; Cardiovascular Diseases; Cerebrum; Cholesterol; Class; Clinical Data; Clinical Trials; Cognitive; Data; Dementia; Development; Diet; Disease; Dose; Elderly; Event; Functional disorder; Goals; Guidelines; Heart Diseases; Hippocampus (Brain); Impaired cognition; In Vitro; Investigation; Lead; Learning; Life; Long-Term Potentiation; Maintenance; Mediating; Memory; Memory impairment; Modification; Molecular; Mus; Neurobiology; Neurons; Neurotransmitter Receptor; Pathology; Pathway interactions; Permeability; Pharmaceutical Preparations; Phosphorylation; Plasma; Plastics; Positioning Attribute; Prevalence; Prevention; Process; Production; Property; Prospective Studies; Protein Biosynthesis; Protein Overexpression; Public Health; Reporting; Retrospective Studies; Sampling; Signal Transduction; Signaling Molecule; Simvastatin; Slice; Staging; Synapses; Synaptic plasticity; Testing; Thinking; Toxic effect; Transgenic Organisms; Vascular Diseases; Work; atorvastatin; base; cholesterol biosynthesis; cognitive function; design; experience; feeding; in vivo; inhibitor/antagonist; insight; isoprenoid; lipophilicity; mevalonate; mouse model; mutant; novel; presenilin; prevent; protective effect; rosuvastatin; sex; trafficking

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.

描述（由申请人提供）：该项目的长期目标是阐明他汀类药物可以预防阿尔茨海默氏病（AD）的细胞和分子机制。他汀类药物是抑制胆固醇生物合成的一类药物。目前，超过3600万美国人正在服用他汀类药物以降低血浆胆固醇水平并预防心脏病。有趣的是，虽然回顾性研究表明，接受他汀类药物的人的AD患病率降低，但前瞻性研究报告了不同的结果。因此，临床数据中的差异激发了新的研究，以定义汀类药物影响认知功能的基本机制。在美国，超过500万人居住在广告中，没有令人满意的治疗方法可以减慢或扭转这种疾病，这强调了阐明他汀类药物治疗AD的好处的巨大需求。正在进行的临床试验（例如降低胆固醇剂（辛伐他汀））对AD的缓慢进展（classicaltrials.gov标识符：NCT00053599）等临床试验进一步强调了这一点。尽管他汀类药物在AD中的有益作用得到了研究表明，他汀类药物较低的胆固醇水平并降低淀粉样蛋白β（AB）的产量，但新出现的证据表明，他汀类药物的保护作用超出了降低胆固醇和AB水平。最近，我们已经表明，辛伐他汀在AD的小鼠模型中挽救了学习和记忆缺陷，而不会影响脑胆固醇和AB水平，但会增加与记忆形成和突触可塑性有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/潜在认知作用； b）他汀类药物的保护作用是由多种途径介导的，其中大多数与胆固醇无关； c）他汀类药物在AB水平降低的疗效取决于他汀类药物治疗开始时疾病的阶段以及他汀类药物的选择和剂量； D）直接神经元作用可能需要汀类药物进入大脑。这些假设将通过在体内和体外的行为，电生理学和生化方法的组合通过三个特定目标进行测试：1）确定不同汀类药物在调节AD小鼠模型中类似AD样行为和病理学方面的疗效。将评估三种汀类药物（辛伐他汀，阿托伐他汀和苏伐他汀），具有不同的亲脂性和血脑屏障（BBB）渗透率。 2）研究他汀类药物治疗对小鼠海马切片突触可塑性的影响。将采用电生理方法来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2的发现，原发性神经元培养物将用于更详细的机械研究，以定义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的机制提供重大洞察力，以便开发出新的疗法来对抗AD。公共卫生相关性：新兴证据表明，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，可防止阿尔茨海默氏病（AD）的发展，这是老年人痴呆症的主要原因。该项目旨在结合行为，电生理和生化方法的组合来阐明他汀类药物发挥抗AD效应的细胞和分子机制。该项目的结果可能会导致对抗广告的新疗法。