Mitochondrial Fission and Fusion in Alzheimer Disease

描述（由申请人提供）：AD 大脑的早期变化包括突触丧失。 AB 被认为在 AD 的发病机制中发挥着核心作用，它与树突棘结合并导致突触功能障碍。然而，AB 引起的突触功能障碍和脊柱损失的机制尚未确定。值得注意的是，突触末端具有丰富的线粒体，在这些位点发挥着不可或缺的作用。沿着这个思路，线粒体功能障碍是 AD 神经元的早期显着特征。线粒体是经历持续裂变和融合事件的动态细胞器，其受到涉及大动力相关 GTP 酶的机制的调节，这些 GTP 酶发挥相反的作用，例如动力样蛋白 1 (DLP1) 和 Fis1 用于裂变，以及线粒体融合素（Mfn1 和 Mfn2C）和 OPA1 用于融合。这些线粒体裂变和融合蛋白不仅控制线粒体的数量和形态，还控制线粒体的分布和功能。事实上，线粒体裂变/融合平衡以及形态和分布的缺陷有可能导致局部能量和钙失衡，这尤其会损害神经元等极化细胞，导致细胞功能障碍和死亡。我们的初步研究表明，AD神经元和成纤维细胞中通常对线粒体形态和分布的严格调控受到损害，这可能是由AB诱导的线粒体裂变/融合蛋白的差异表达引起的。我们的中心假设是 AB 通过其对线粒体裂变/融合的毒性作用诱导线粒体功能障碍和突触异常。我们将追求四个目标： 目标 1) ADDLs 通过其对体外线粒体裂变/融合的毒性作用诱导线粒体功能障碍和突触异常；目的2）探讨ADDL诱导DLP1降低的机制； Aim3) 突变型 PS1 至少部分通过与 DLP1 的相互作用以及线粒体裂变/融合平衡受损而导致线粒体异常和神经元功能障碍；目标 4) DLP1 减少是体内线粒体异常和突触丧失的基础。公共健康相关性：AB 引起的突触功能障碍和脊柱缺失是一种早期变化，也是 AD 相关认知缺陷的最有力相关因素，但其潜在机制尚未确定。众所周知，线粒体在突触末梢中起着不可或缺的作用，线粒体裂变/融合的平衡对于线粒体的分布和功能至关重要。我们的初步研究表明线粒体裂变/融合平衡受损可能参与AD的发病机制，在本申请中，我们建议研究AB是否通过其对线粒体裂变和融合平衡的毒性作用导致突触功能障碍和线粒体异常。

DESCRIPTION (provided by applicant): Early changes in AD brain include loss of synapses. AB, considered to have a central role in the pathogenesis of AD, bind to dendritic spines and cause synaptic dysfunction. However, the mechanisms responsible for AB-induced synaptic dysfunction and spine loss are not firmly established. Notably, synaptic terminals have abundant mitochondria which play an indispensable role at these sites. Along this line, mitochondrial dysfunction is an early prominent feature of AD neurons. Mitochondria are dynamic organelles that undergo continual fission and fusion events which are regulated by a machinery involving large dynamin-related GTPase that exert opposing effects, e.g., dynamin-like protein 1 (DLP1) and Fis1 for fission, and mitofusins (Mfn1 and Mfn2C) and OPA1 for fusion. These mitochondria fission and fusion proteins control not only mitochondrial number and morphology but also mitochondrial distribution and function. Indeed, defects in the mitochondrial fission/fusion balance and thus, the morphology and distribution have the potential to cause localized energy and calcium imbalance, which is especially damaging to polarized cells such as neurons, resulting in cellular dysfunction and death. Our preliminary studies suggest that the normally strict regulation of mitochondria morphology and distribution is impaired in AD neurons and fibroblasts which may be caused by differential expression of mitochondrial fission/fusion proteins induced by AB. Our central hypothesis is that AB induces mitochondrial dysfunction and synaptic abnormalities via its toxic effect on mitochondrial fission/fusion. Four aims will be pursued: Aim1) ADDLs induce mitochondrial dysfunction and synaptic abnormalities via its toxic effect on mitochondrial fission/fusion in vitro; Aim2) To Explore the Mechanisms of ADDL-induced DLP1 Reduction; Aim3) mutant PS1 causes mitochondrial abnormalities and neuronal dysfunction at least in part through its interaction with DLP1 and impaired balance in mitochondrial fission/fusion; Aim 4) DLP1 reduction underlies mitochondrial abnormalities and synaptic loss in vivo. PUBLIC HEALTH RELEVANCE: AB-caused synaptic dysfunction and spine loss is an early change and the most robust correlate of AD- associated cognitive deficits, however the underlying mechanism is not firmly established. It is known that mitochondria play an indispensable role in synaptic terminals and the balance of mitochondrial fission/fusion is critical for mitochondrial distribution and function. Our preliminary studies suggest the potential involvement of an impaired balance of mitochondrial fission/fusion in the pathogenesis of AD, in this application, we propose to investigate whether AB cause synaptic dysfunction and mitochondrial abnormalities via its toxic effect on the balance of mitochondrial fission and fusion.