Role of Cyclophilin D in Abeta-induced synaptic injury

线粒体和突触功能障碍是阿尔茨海默病（AD）的早期病理特征。 修复它的潜在机制和策略仍不清楚。最近的研究强调了 AD发病机制中的线粒体失活和早期突触线粒体缺陷。早期突触线粒体 损伤表明AD神经元可能已经遭受多年的伤害，这可能有助于解释 目前淀粉样蛋白假说的局限性。因此，抑制/减弱AD-和ApoA-诱导的策略是有效的。 除了线粒体毒性外，脑中的维生素A水平和改善认知功能对于预防 和/或通过改善线粒体功能在非常早期阶段停止AD。亲环素D（CypD）在细胞凋亡中起着重要的作用。 在打开线粒体膜渗透性转换孔（mPTP）导致细胞死亡中的作用。CypD- 介导的mPTP增强Ablation和氧化应激诱导的线粒体、突触和认知功能障碍， AD小鼠模型。CypD的消除导致对AD中的阿托伐他汀毒性的持久终身保护 提示CypD是AD治疗药物开发的潜在靶点。但 CypD与AD衍生的线粒体缺陷的直接联系仍然是难以捉摸的。目前尚不清楚CypD增强是否 mPTP和信号转导有助于AD相关的线粒体缺陷，包括线粒体膜电位的改变。 形态学、动力学和功能，CypD如何调节线粒体动力学，以及阻断CypD是否 挽救AD线粒体损伤。为了探索AD特异性线粒体缺陷的相关机制，我们 最近产生了线粒体胞质杂种（cybrid）神经元细胞系， 将MCI、AD和认知正常的年龄匹配受试者的血小板线粒体转化为线粒体DNA （mtDNA）耗尽的神经元细胞。这些人AD胞质杂种神经元系概括了线粒体结构 和AD中观察到的功能变化。我们发现CypD在MCI和AD胞质杂交细胞中表达增加。 重要的是，阻断CypD表达或抑制CypD活性可以恢复线粒体形态， 动力学（融合/裂变平衡）和功能。我们假设CypD介导的mPTP 改变线粒体的分布/形态和功能，线粒体动力学的平衡，这可能 是AD相关的线粒体和突触缺陷的基础。CypD的封锁将对 线粒体和突触损伤。这个项目的总体目标是获得新的洞察CypD在AD中的作用 特异性线粒体缺陷，并探索/验证一类新的小分子CypD抑制剂， 线粒体和认知功能障碍该项目的成果将对世界经济产生重大影响。 通过确定预防和治疗干预的新靶点，研究AD研究领域。

Mitochondrial and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD) affected brain. The underlying mechanisms and strategies to repair it remain unclear. Recent studies have highlighted the role of mitochondrial Aß and early synaptic mitochondrial defects in AD pathogenesis. The early synaptic mitochondrial damage suggests that AD neurons may have already suffered harm for years, which may help explain the limitations to current amyloid hypothesis. Thus, strategies that suppress/attenuate AD- and Aß-induced mitochondrial toxicity in addition to Aß levels in the brain and improve cognitive function are critical for preventing and/or halting AD at a very early stage by improving mitochondrial function. Cyclophiiin D (CypD) plays a central role in opening the mitochondrial membrane permeability transition pore (mPTP) leading to cell death. CypD- mediated mPTP potentiates Aß- and oxidative stress-induced mitochondrial, synaptic, and cognitive dysfunction in the AD mouse model. Abrogation of CypD results in persistent life-long protection against Aß toxicity in an AD mouse model, suggesting that CypD is a potential target of the drug development for AD therapy. However, a direct link of CypD to AD-derived mitochondrial defects remains elusive. It is unclear whether CypD-potentiated mPTP and signal transduction contribute to AD-related mitochondrial defects including alterations in mitochondrial morphology, dynamics, and function, how CypD regulates mitochondrial dynamics, and whether blocking CypD rescues AD mitochondrial injury. To explore the mechanism associated with AD-specific mitochondrial defects, we have recently generated transmitochondrial cytoplasmic hybrid (cybrid) neuronal cell lines with incorporated platelet mitochondria from MCI, AD, and cognitively normal aged-matched subjects into mitochondrial DNA {mtDNA)-depleted neuronal cells. These human AD cybrid neuronal lines recapitulate mitochondrial structural and functional changes observed in AD. We found increased expression of CypD in MCI and AD cybrid cells. Importantly, blockade of CypD expression or inhibiting CypD activity restored mitochondrial morphology, dynamics (fusion/fission balance) and function in AD cybrid cells. We hypothesize that CypD-mediated mPTP alters mitochondrial distribution/morphology and function, balance of mitochondrial dynamics, which is likely to underlie AD-related mitochondrial and synaptic defects. Blockade of CypD will have a protective effect on mitochondrial and synaptic injury. The overall goal of this project is to gain new insight into the role of CypD in AD specific mitochondrial defects and to explore/validate a new class of small molecule CypD inhibitor for rescuing mitochondrial and cognitive dysfunction. The outcomes of this project will have a significantly high impact on the AD research field by identifying new targets for preventive and therapeutic intervention.