Abnormal Mitochondrial Dynamics and Mitochondrial Dysfunction in Alzheimer's Dise

阿尔茨海默病中的线粒体动力学异常和线粒体功能障碍

基本信息

批准号：
9261605
负责人：
Xiongwei Zhu
金额：
$ 41.52万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2019-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Multiple lines of evidence indicate that mitochondrial dysfunction plays a critical role in the pathogenesis of Alzheimer disease; however, the underlying molecular mechanism and its role in AD pathogenesis remain poorly understood. Mitochondria are dynamic organelles that undergo continuous fission and fusion. Our recent in vitro studies suggest that abnormal mitochondrial dynamics likely contributes to mitochondrial dysfunction and synaptic/neuronal dysfunction in AD. Based on these studies, we hypothesized that impaired balance in mitochondrial fission/fusion plays a critical role in the pathogenesis of AD by causing excessive mitochondrial fragmentation and redistribution as well as causes mitochondrial ultrastructural defects and dysfunction which in turn adversely affects neuronal functions including synaptic dysfunction and cognitive/behavioral deficits in AD. However, due to the limitation of in vitro cell culture models, it remains to be determined whether it is mitochondrial fragmentation or elongation that occurs in vivo since swollen mitochondrial in AD or APP mice may demonstrate increased size and/or length. Moreover, it also remains to be determined whether abnormal mitochondrial dynamics is causally involved in mitochondrial/synaptic dysfunction and cognitive deficits in APP mice in vivo. Our preliminary results demonstrated mitochondrial dysfunction, fragmented mitochondria, and decreased expression of mitochondrial fission/fusion proteins in the hippocampus of 3 month-old CRND8 APP transgenic mice, suggesting an altered mitochondrial dynamics early in the disease process. More importantly, we were able to enhance mitochondrial fusion in vivo by overexpressing Mfn2 expression in hippocampus, which enables us to address these critical gaps in our knowledge in vivo. Therefore, we propose to cross these Mfn2 mice with CRND8 APP transgenic mice and determine how normalization of mitochondrial dynamics will affect mitochondrial function, and neuronal/synaptic dysfunction and pathological/behavioral/cognitive deficits in CRND8 mice. The goal is to obtain a definite answer on the involvement of mitochondrial fragmentation or elongation in APP mice and to determine the causal role of mitochondrial dynamics in mitochondrial/neuronal dysfunction and cognitive/behavioral deficits in AD mouse models, which will also serve as a proof-of-concept study for Mfn2-directed therapy for AD. To complement the in vivo studies, we will determine the causal involvement of abnormal mitochondrial dynamics in Abeta-induced mitochondrial/neuronal function and further pursue mechanisms underlying Abeta-induced changes in mitochondrial dynamics and how Mfn2 overexpression rescues Abeta-induced mitochondrial deficits.

描述（由申请人提供）：多种证据表明线粒体功能障碍在阿尔茨海默氏病的发病机理中起关键作用。然而，潜在的分子机制及其在AD发病机理中的作用仍然很少理解。线粒体是经历连续裂变和融合的动态细胞器。我们最近的体外研究表明，异常的线粒体动力学可能导致AD中的线粒体功能障碍和突触/神经元功能障碍。 Based on these studies, we hypothesized that impaired balance in mitochondrial fission/fusion plays a critical role in the pathogenesis of AD by causing excessive mitochondrial fragmentation and redistribution as well as causes mitochondrial ultrastructural defects and dysfunction which in turn adversely affects neuronal functions including synaptic dysfunction and cognitive/behavioral deficits in AD.但是，由于体外细胞培养模型的局限性，由于在AD或APP小鼠中肿胀的线粒体肿胀，在体内发生的线粒体碎裂还是伸长尚可能表现出大小和/或长度的增加。此外，还尚待确定是否存在异常的线粒体动力学与体内App Mice中的线粒体/突触功能障碍和认知缺陷有关。我们的初步结果表明线粒体功能障碍，线粒体碎片以及在疾病过程中早期的线粒体动力学改变的3个月大的CRND8 APP转基因小鼠的海马中线粒体裂变/融合蛋白的表达降低。更重要的是，我们能够通过过表达海马中的MFN2表达来增强体内的线粒体融合，这使我们能够解决我们在体内知识中的这些关键差距。因此，我们建议将这些MFN2小鼠与CRND8 APP转基因小鼠穿越这些MFN2小鼠，并确定线粒体动力学的归一化如何影响线粒体功能，以及神经/突触功能障碍以及病理/行为/行为/行为/认知缺陷。目的是获得有关APP小鼠中线粒体碎裂或伸长的参与的明确答案，并确定线粒体动力学在线粒体/神经元功能障碍和AD小鼠模型中的认知/行为缺陷中的因果作用，这也将作为对MFN2-for for Mfn2-forsive for Mfn2-forsive for Mfn2-forsive for Mfn2-forsive for Mfn2-forsive for for Mfn2-forsive for for for Mfn2-forsive for for for for for Mfn2-forsive for for for for for for mfn2-for for for for for for mfn2 direction。为了补充体内研究，我们将确定线粒体动力学异常在Abeta诱导的线粒体/神经元功能中的因果关系，并追求Abeta诱导的线粒体变化的基础机制。