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

描述（由申请人提供）：我们拟议研究的长期目标是了解线粒体功能障碍阿尔茨海默病（AD）发病机制的分子基础，并开发神经保护策略以延迟或预防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蛋白和线粒体结构和功能异常是严重参与突触的损失和认知能力下降，在阿尔茨海默病（AD）患者。多条证据表明，Ab和过度磷酸化的tau蛋白直接导致AD发病机制中的线粒体功能障碍和氧化应激。1)2）近年来的研究发现，在AD死后模型和表达Ab的转基因小鼠模型和细胞系中，线粒体分裂基因的mRNA和蛋白水平增加，融合基因减少，导致线粒体动力学异常; 3）其他一些研究发现Ab减少了总的运动线粒体，损害线粒体轴突运输，特别是顺行运输，抑制突触ATP的产生;并导致AD神经元中的突触变性，以及4）此外，在来自AD患者和Ab和tau的转基因小鼠模型的神经元中，GT3蛋白、Drp 1与Ab和过度磷酸化的tau相互作用。这些发现导致的假设，Drp1与抗体和过度磷酸化的tau蛋白的相互作用触发线粒体分裂，通过增强Drp1酶活性，并导致过度的线粒体片段化，最终选择性地在AD神经元的神经元功能障碍。 本申请的目的是1）确定Drp1与Ab和过度磷酸化tau的相互作用是否随着疾病进展和发病机制而增加; 2）进一步了解这种相互作用如何影响Drp1酶活性和AD神经元中的线粒体形态、分布和功能; 3）此外，Drp1的部分缺失是否减少Ab和过度磷酸化tau诱导的线粒体片段化，神经元损伤和突触功能障碍。本申请中提出的实验的结果将为理解Drp1与Ab和磷酸化tau在AD进展和发病机制中的相互作用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剂以减少AD患者中Ab和过度磷酸化tau诱导的病理具有意义。 公共卫生相关性：线粒体功能障碍是阿尔茨海默病（AD）的主要标志。线粒体在神经元中起着重要的作用，维持着线粒体分裂与融合的平衡。这项研究的目的是确定Drp1与淀粉样蛋白β和过度磷酸化tau蛋白的相互作用是否会影响Drp1的酶活性并改变AD神经元中的线粒体形态、分布和功能，以及Drp1的部分缺失是否会降低淀粉样蛋白β和过度磷酸化tau蛋白诱导的线粒体碎片化、神经元损伤和突触功能障碍。

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. PUBLIC HEALTH RELEVANCE: Mitochondrial dysfunction is a major hallmark of Alzheimer's disease (AD). Mitochondria play an important role in neurons and maintain the balance of mitochondrial fission and fusion. The objective of the proposed research is to determine whether Drp1 interactions with amyloid beta and with hyperphosphorylated tau affect Drp1 enzymatic activity and alter mitochondrial morphology, distribution, and function in AD neurons, and whether partial loss of Drp1 decreases amyloid beta and hyperphosphorylated tau-induced mitochondrial fragmentation, neuronal damage, and synaptic dysfunction.