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病的发病机制中发挥着关键作用；然而，潜在的分子机制及其在 AD 发病机制中的作用仍然知之甚少。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。基于这些研究，我们假设线粒体裂变/融合平衡受损在 AD 的发病机制中起着关键作用，它会导致线粒体过度破碎和重新分布，并导致线粒体超微结构缺陷和功能障碍，进而对神经元功能（包括突触功能障碍）产生不利影响AD 中的认知/行为缺陷。然而，由于体外细胞培养模型的限制，体内是否发生线粒体断裂或伸长仍有待确定，因为 AD 或 APP 小鼠中肿胀的线粒体可能表现出尺寸和/或长度的增加。此外，线粒体动力学异常是否与 APP 小鼠体内线粒体/突触功能障碍和认知缺陷有关，还有待确定。我们的初步结果表明，3 个月大的 CRND8 APP 转基因小鼠的海马体存在线粒体功能障碍、线粒体碎片以及线粒体裂变/融合蛋白表达减少，这表明在疾病过程的早期线粒体动力学发生了改变。更重要的是，我们能够通过在海马中过度表达 Mfn2 来增强体内线粒体融合，这使我们能够解决体内知识中的这些关键空白。因此，我们建议将这些 Mfn2 小鼠与 CRND8 APP 转基因小鼠杂交，并确定线粒体动力学正常化将如何影响 CRND8 小鼠的线粒体功能、神经元/突触功能障碍和病理/行为/认知缺陷。目标是获得APP小鼠线粒体断裂或伸长参与的明确答案，并确定线粒体动力学在AD小鼠模型中线粒体/神经元功能障碍和认知/行为缺陷中的因果作用，这也将作为证据Mfn2 定向治疗 AD 的概念研究。为了补充体内研究，我们将确定异常线粒体动力学与 Abeta 诱导的线粒体/神经元功能的因果关系，并进一步探究 Abeta 诱导的线粒体动力学变化的潜在机制以及 Mfn2 过表达如何挽救 Abeta 诱导的线粒体缺陷。