NEUROPROTECTIVE EFFECTS OF DIMEBON IN ALZHEIMER'S DISEASE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 阿尔茨海默病(AD)是一种进行性神经退行性疾病，其特征是年龄相关性记忆丧失和多种认知功能障碍。阿尔茨海默病的主要病理特征是细胞外淀粉样β蛋白斑块和细胞内神经原纤维缠结。突触损伤和线粒体氧化损伤已被报道为AD的早期事件。最近的A和线粒体研究表明，线粒体靶向治疗干预在延缓老年人AD进展和治疗AD患者方面可能是有效的。在最近对来自俄罗斯的AD患者的临床试验进行的研究中，Doody和他的同事发现，Dimebon是安全的，耐受性良好，并显著改善了轻至中度AD患者的临床病程。然而，狄美朋的线粒体保护机制仍不清楚。在目前的试点拨款申请中，我们建议研究AD转基因小鼠和野生型小鼠经线粒体靶向抗氧化剂Diebon处理和未处理的胚胎和成年原代神经元中的线粒体动力学、线粒体运输和轴突生长。我们提出了两个具体目标。利用‘Livecell成像技术’和共聚焦显微镜，在目标1中，我们将研究AD转基因小鼠胚胎和成年原代神经元的线粒体动力学。目的2将评估线粒体和迪美朋的神经保护作用。这一试验性应用的结果将为理解Diebon在AD中的神经保护作用提供新的见解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Alzheimer's disease (AD) is a progressive, neurodegenerative disorder, characterized by an agedependent loss of memory and an impairment of multiple cognitive functions. The major pathological features of AD are extracellular amyloid beta (A¿) plaques and intracellular neurofibrillary tangles. Synaptic damage and mitochondrial oxidative damage have been reported as early events in AD. Recent A¿ and mitochondrial studies suggest that mitochondrial targeted therapeutic interventions may be effective in delaying AD progression in elderly individuals and in treating AD patients. In a recent study of clinical trials of AD patients from Russia, Doody and colleagues found that Dimebon was safe, well tolerated, and significantly improved the clinical course of patients with mild-to-moderate AD. However, mitochondrial protective mechanisms of Dimebon are still unclear. In the present pilot grant application, we propose to study mitochondrial dynamics, mitochondrial trafficking, and neurite outgrowth in embryonic and adult primary neurons from AD transgenic mice and wildtype mice treated and untreated with mitochondrial targeted antioxidant, Dimebon. We propose 2 Specific Aims. Using 'livecell imaging technology' and confocal microscopy, in Aim 1 we will investigate mitochondrial dynamics in embryonic and adult primary neurons from AD transgenic mice. Aim 2 will assess mitochondrial and neuroprotective effects of Dimebon. The outcome of this pilot application will provide new insights in understanding the neuroprotective effects of Dimebon in AD.