Modulation of Alzheimer's Amyloidosis by Statins

他汀类药物对阿尔茨海默病淀粉样变性的调节

• 批准号: 6600349
• 负责人: SUZANA S PETANCESKA
• 金额: $ 22.09万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6600349
• 关键词: Alzheimer's disease; amyloid proteins; amyloidosis; apolipoprotein E; atorvastatin; blood brain barrier; brain disorder chemotherapy; cholesterol; disease /disorder model; genetically modified animals; inflammation; laboratory mouse; metabolism disorder chemotherapy; microglia; neuroimmunomodulation; neuropathology; neurotoxicology; nonhuman therapy evaluation; pathologic process; simvastatin; tissue /cell culture

DESCRIPTION (provided by applicant): Cerebral accumulation of Amyloid beta (Abeta) peptides is an early event in establishing of Alzheimer's disease (AD) pathology. Based on the epidemiological evidence pointing to a link between cholesterol metabolism and AD and the numerous laboratory studies implicating cholesterol in the process of Abeta production and accumulation, it is now believed that cholesterol-lowering therapies will be of value as disease modifying agents. Several epidemiological studies revealed that statin use for the treatment of coronary arterial disease is associated with a decreased prevalence or a decreased risk of developing AD. The major objectives of this proposal are: to test the ability of different statins to delay the onset or retard the progression of brain Abeta deposition in the PSAPP transgenic mouse model of Alzheimer's amyloidosis, and to investigate the mechanisms by which statin treatment modulates brain Abeta accumulation. Our goal is to examine how the lipid-lowering as well as the anti-inflammatory/immunomodulatory activities of statins contribute to their effect on brain Abeta accumulation. To this end we will employ in vivo experimental paradigms using the PSAPP transgenic mouse model of Alzheimer's amyloidosis, as well as in vitro experimental paradigms using microglial and neuronal cultures. In the first specific aim we will compare the relative efficacy with which statins with different BBB permeability attenuate early as well as advanced Abeta deposition. We will then examine how statin treatments modulate APP processing and ApoE expression in brain (specific aim 2). Finally, we will evaluate the effects of statins on the inflammatory response in brain in the context of different paradigms of microglial activation and we will test their ability to prevent or attenuate Abeta-induced microglial neurotoxicity (specific aim 3).

描述（由申请人提供）：淀粉样β（ABETA）肽的脑积累是建立阿尔茨海默氏病（AD）病理学的早期事件。基于表明胆固醇代谢与AD之间的联系的流行病学证据以及涉及胆固醇在Abeta生产和积累过程中的众多实验室研究之间的联系，现在人们认为，降低胆固醇的疗法将具有价值作为修饰药物的价值。几项流行病学研究表明，他汀类药物用于治疗冠状动脉疾病的使用与患病率降低或降低AD的风险有关。该提案的主要目的是：测试不同汀类药物在阿尔茨海默氏症淀粉样变性的PSAPP转基因小鼠模型中延迟或阻碍脑Abeta沉积的发作或阻碍脑abeta沉积的能力，并研究汀类药物治疗调节脑Abeta累积的机制。我们的目标是研究他汀类药物的降低脂质以及抗炎/免疫调节活性如何有助于它们对脑Abeta积累的影响。为此，我们将使用阿尔茨海默氏症淀粉样变性的PSAPP转基因小鼠模型以及使用小胶质细胞和神经元培养物的体外实验范式采用体内实验范式。在第一个特定目的中，我们将比较他汀类药物具有不同BBB渗透率的相对疗效，早期和晚期ABETA沉积。然后，我们将研究他汀类药物治疗如何调节大脑中的应用程序处理和APOE表达（特定目标2）。最后，我们将在小胶质激活范式的情况下评估他汀类药物对大脑炎症反应的影响，并将测试它们预防或衰减Abeta诱导的小胶质细胞神经毒性的能力（特定AIM 3）。