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

描述(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的阿尔茨海默病(AD)发病机制的分子基础，并开发神经保护策略来延迟或预防AD的发生。越来越多的证据表明，淀粉样β蛋白(AB)、过度磷酸化的tau以及线粒体结构和功能的异常与阿尔茨海默病(AD)患者突触丢失和认知功能下降密切相关。一些证据表明，抗体和过度磷酸化的tau在AD发病机制中直接导致线粒体功能障碍和氧化应激。1)几项研究发现，抗体和N-末端tau存在于线粒体膜上，并导致受AD影响的神经元的线粒体功能障碍；2)最近的研究发现，在AD死亡后以及表达抗体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，融合基因降低，从而导致线粒体动力学异常；3)其他几项研究发现，抗体可减少总运动性线粒体，损害线粒体轴突的运输，尤其是顺行转运；抑制突触ATP的产生；并导致AD神经元中突触变性；4)进一步，GTPase蛋白、Drp1与抗体和过度磷酸化的tau在AD患者和转基因小鼠模型的神经元中相互作用。这些发现导致假设，在AD神经元中，Drp1与抗体和过度磷酸化的tau的相互作用通过增强Drp1的酶活性而触发线粒体的分裂，导致线粒体过度碎裂，最终选择性地导致神经元功能障碍。我们的应用目标是1)确定Drp1与抗体和过度磷酸化tau的相互作用是否随着疾病的进展和发病机制而增加；2)进一步了解这种相互作用如何影响Drp1的酶活性以及AD神经元中线粒体的形态、分布和功能；3)此外，是否部分丢失Drp1会减少Ab和过度磷酸化tau诱导的线粒体断裂、神经元损伤和突触功能障碍。这一应用中的拟议实验结果将为理解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学相关性提供新的见解，其结果可能对开发线粒体疗法来减少Ab和过度磷酸化tau诱导的AD患者的病理具有一定的意义。

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.