Mitochondrial Fission and Fusion in Alzheimer Disease

描述(申请人提供)：AD大脑的早期变化包括突触丢失。AB被认为在AD的发病机制中起核心作用，它与树突棘结合并导致突触功能障碍。然而，AB诱导的突触功能障碍和脊椎丢失的机制尚未确定。值得注意的是，突触终末有丰富的线粒体，在这些部位发挥着不可或缺的作用。沿着这条线，线粒体功能障碍是AD神经元的早期显著特征。线粒体是经历连续分裂和融合事件的动态细胞器，参与调节的机制包括发挥相反作用的大型动力蛋白相关GTP酶，例如用于分裂的动力素样蛋白1(DLP1)和FIS1，以及用于融合的有丝分裂蛋白(Mfn1和Mfn2C)和OPA1。这些线粒体分裂和融合蛋白不仅控制线粒体的数量和形态，而且还控制线粒体的分布和功能。事实上，线粒体分裂/融合平衡的缺陷以及线粒体的形态和分布可能会导致局部的能量和钙失衡，这对神经元等极化细胞尤其有害，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对线粒体形态和分布的严格调控受到损害，这可能是由于AB诱导的线粒体分裂/融合蛋白的差异表达所致。我们的中心假设是AB通过对线粒体分裂/融合的毒性作用而导致线粒体功能障碍和突触异常。Aim1)ADDLS通过对线粒体分裂/融合的毒性作用在体外诱导线粒体功能障碍和突触异常；AIM2)探讨ADDR诱导DLP1减少的机制；Aim3)突变型PS1至少部分通过与DLP1相互作用和破坏线粒体分裂/融合平衡而导致线粒体异常和神经元功能障碍；目的4)DLP1减少是体内线粒体异常和突触丧失的基础。公共卫生相关性：AB引起的突触功能障碍和脊柱丢失是AD相关认知缺陷的早期变化和最强有力的相关性，然而潜在的机制尚未确定。众所周知，线粒体在突触末端起着不可或缺的作用，线粒体分裂/融合的平衡对线粒体的分布和功能至关重要。我们的初步研究表明，线粒体分裂/融合平衡受损可能参与了AD的发病机制，在这一应用中，我们建议探讨AB是否通过对线粒体分裂/融合平衡的毒性作用而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.