RAGE and mitochondrial degeneration in diabetes

 描述(申请人提供)：线粒体功能障碍和突触损伤是阿尔茨海默病(AD)-6-10和糖尿病影响的大脑的早期特征。糖尿病对大脑有负面影响，增加了患抑郁症和痴呆症的风险。在神经元中，突触处的线粒体对于维持突触功能和通过正常的线粒体动力学、适当的分布和运输、能量代谢和突触钙调节来维持突触功能和传递至关重要。线粒体动力学的失衡导致氧化应激和高血糖引起的线粒体形态和功能的改变。其潜在的分子和细胞机制还知之甚少。RAGE(晚期糖基化终产物受体，AGEs)是免疫球蛋白超家族的多配体受体。RAGE是AGEs、S100/钙颗粒或淀粉样β蛋白的信号转导受体。RAGE及其配体的相互作用增加了氧化应激、炎症、A？堆积，并损害了突触功能和学习记忆。然而，RAGE对糖尿病(DM)患者线粒体和突触功能的影响仍不清楚。目前尚不清楚RAGE是否是年龄和糖尿病诱导的线粒体和突触应激的重要介质；RAGE依赖的信号转导是否以及如何导致DM的线粒体和突触结构和功能的改变。在我们的初步研究中，我们揭示了一些与RAGE调控线粒体有关的新发现。首先，神经元RAGE的基因缺失可以缓解年龄引起的突触功能障碍。阻断RAGE信号挽救了高糖诱导的线粒体改变。其次，GLOBAL RAGE的基因缺失挽救了糖尿病小鼠脑内线粒体形态/功能异常和突触损伤，并诱导了促炎介质。最后，RAGE与DLP1(Dynamin-like Protein 1)存在生化相互作用，提示DLP1是一种新的底物，介导RAGE对线粒体分布的影响。此外，抑制过度的线粒体分裂或RAGE可减弱DM诱导的促炎细胞因子和趋化因子的诱导。这些发现使我们推测，在糖尿病中，AGEs和促炎性RAGE配体的慢性和持续积聚，以及RAGE的上调，扰乱了线粒体的结构和功能，并导致氧化应激，导致DM患者突触线粒体功能障碍和突触损伤。这项提议将解决RAGE是否在糖尿病引起的线粒体和突触损伤中起关键作用，以及阻断RAGE是否恢复线粒体和神经元功能的根本问题。

 DESCRIPTION (provided by applicant): Mitochondrial dysfunction and synaptic damage are early features of Alzheimer's disease (AD)-6- 10 and diabetes-affected brains. Diabetes negatively affects the brain, increasing the risk of depression and dementia. In neurons, mitochondria at synapses are vital for maintenance of synaptic function and transmission through normal mitochondrial dynamics, proper distribution and trafficking, energy metabolism, and synaptic calcium modulation. Imbalance of mitochondria dynamics contributes to oxidative stress- and hyperglycemia-induced alterations in mitochondrial morphology and function. The underlying molecular and cellular mechanisms are poorly understood. RAGE (Receptor for Advanced Glycation Endproducts, AGEs) is a multiligand receptor of the immunoglobulin superfamily. RAGE functions as a signal transducing cell surface acceptor site for AGEs, S100/calgranuline, or amyloid-beta peptide (Aß). Interaction of RAGE and its ligands increases oxidative stress, inflammation, Aß accumulation, and impairs synaptic function and learning memory. However, the impact of RAGE on mitochondrial and synaptic function in diabetes mellitus (DM) remains unknown. It is unclear whether RAGE is important mediator for AGE- and diabetes-induced mitochondrial and synaptic stress; whether and how RAGE-dependent signal transduction contributes to alterations in mitochondrial and synaptic structure and function in DM. In our preliminary studies, we have revealed a number of novel findings related to the regulation of mitochondria by RAGE. First, genetic depletion of neuronal RAGE alleviates AGE-induced synaptic dysfunction. Blockade of RAGE signaling rescued high glucose-induced mitochondrial alterations. Second, genetic depletion of global RAGE rescued abnormal mitochondrial morphology/function and synaptic injury in diabetes mouse brains as well as induction of proinflammatory mediators. Finally, RAGE exhibited biochemical interaction with DLP1 (dynamin-like protein 1), suggesting that DLP1 serves as a novel substrate to mediate the effect of RAGE on mitochondrial distribution. Further, inhibition of excessive mitochondrial fission or RAGE attenuated DM-induced induction of proinflammatory cytokines and chemokine. These findings lead us to hypothesize that in diabetes, chronic and sustained accumulation of AGEs and proinflammatory RAGE ligands, and upregulation of RAGE, perturbs mitochondrial structure and function, and oxidative stress, leading to synaptic mitochondrial dysfunction and synaptic injury in DM. This proposal will address the fundamental questions of whether RAGE is a key player in diabetes-induced mitochondrial and synaptic injury and whether blockade of RAGE restores mitochondrial and neuronal function.