Dynamin-Related Protein 1 and Mitochondrial Fragmentation in Alzheimer's Disease

描述（由申请人提供）：我们提出的研究的长期目标是了解线粒体功能障碍在阿尔茨海默病（AD）发病机制中的分子基础，并制定神经保护策略来延迟或预防AD的发作。越来越多的证据表明，淀粉样蛋白β (Ab)、过度磷酸化的tau和线粒体结构和功能异常与阿尔茨海默病（AD）患者的突触丧失和认知能力下降密切相关。多项证据表明，Ab和过度磷酸化的tau在AD发病过程中直接导致线粒体功能障碍和氧化应激。1)多项研究发现Ab和n端tau蛋白存在于线粒体膜中，导致AD神经元线粒体功能障碍；2)近期研究发现AD死后和转基因小鼠模型及表达Ab的细胞系线粒体裂变基因mRNA和蛋白水平升高，融合基因水平降低，导致线粒体动力学异常；3)其他几项研究发现，Ab减少线粒体总运动，损害线粒体轴突运输，特别是顺行运输；抑制突触ATP的产生；4)此外，GTPase蛋白Drp1与AD患者及Ab和tau转基因小鼠模型的神经元中Ab和过度磷酸化的tau相互作用。这些发现导致假设Drp1与Ab和过度磷酸化的tau相互作用通过增强Drp1酶活性触发线粒体分裂，并导致线粒体过度断裂，最终选择性地导致AD神经元神经元功能障碍。我们申请的目的是1)确定Drp1与Ab和过度磷酸化的tau的相互作用是否随着疾病的进展和发病机制而增加；2)进一步研究这种相互作用如何影响AD神经元中Drp1酶活性和线粒体形态、分布和功能；3)此外，Drp1的部分缺失是否会降低Ab和过度磷酸化的tau诱导线粒体断裂、神经元损伤和突触功能障碍。本应用程序中提出的实验结果将为理解Drp1与Ab和磷酸化tau相互作用在AD进展和发病机制中的生理相关性提供新的见解，并且结果可能对开发线粒体治疗方法以减少AD患者Ab和过度磷酸化tau诱导的病理具有启示意义。

DESCRIPTION (provided by applicant): The long-term goal of our proposed research is to understand molecular basis of mitochondrial dysfunction Alzheimer's disease (AD) in pathogenesis and to develop neuroprotective strategies to delay or prevent the onset of AD. Increasing evidence suggests that amyloid beta (Ab), hyperphosphorylated tau and mitochondrial structural and functional abnormalities are critically involved in the loss of synapses and cognitive decline, in patients with Alzheimer's disease (AD). Several lines of evidence suggests that Ab and hyperphosphorylated tau are directly responsible for causing mitochondrial dysfunction and oxidative stress in AD pathogenesis. 1) Several studies found Ab and N-terminal tau in mitochondrial membranes and causing mitochondrial dysfunction in neurons affected by AD; 2) recent studies found increased mRNA and protein levels of the mitochondrial fission genes and decreased fusion genes in AD postmortem and transgenic mouse models and cell-lines that express Ab, causing abnormal mitochondrial dynamics; 3) several other studies found that Ab reduces total motile mitochondria, impairs mitochondrial axonal transport, particularly anterograde transport; inhibits synaptic ATP production; and causes synaptic degeneration in AD neurons and 4) further, GTPase protein, Drp1 interacted with Ab and hyperphosphorylated tau in neurons from AD patients and transgenic mouse models of Ab and tau. These findings lead to the hypothesis that the interaction of Drp1 with Ab and hyperphosphorylated tau triggers mitochondrial fission by enhancing Drp1 enzymatic activity and causes excessive mitochondrial fragmentation, and ultimate neuronal dysfunction selectively in AD neurons. The objectives of our application are 1) to determine whether Drp1 interactions with Ab and hyperphosphorylated tau increases with disease progression and pathogenesis; 2) further how such interaction affects Drp1 enzymatic activity and mitochondrial morphology, distribution and function in AD neurons; 3) in addition, whether partial loss of Drp1 decreases Ab and hyperphosphorylated tau-induced mitochondrial fragmentation, neuronal damage and synaptic dysfunction. The outcome of the proposed experiments in this application, will provide new insights in understanding the physiological relevance of interactions Drp1 with Ab, and phosphorylated tau in AD progression and pathogenesis and the outcome may have implications to develop mitochondrial therapeutics to reduce Ab and hyperphosphorylated tau-induced pathologies in AD patients.