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)脑损害的早期病理特征。 修复它的潜在机制和战略仍不清楚。最近的研究强调了 线粒体Aç与早期突触线粒体缺陷在AD发病机制中的作用早期突触线粒体 损伤提示AD神经元可能已经遭受了多年的损伤，这可能有助于解释 当前淀粉样蛋白假说的局限性。因此，抑制/减弱AD和A？诱导的策略 线粒体毒性以及大脑中的Aü水平和改善认知功能是预防 和/或通过改善线粒体功能在非常早期阶段阻止AD。环磷蛋白D(CypD)在人类免疫反应中起重要作用 在打开线粒体膜通透性转换孔(MPTP)导致细胞死亡中的作用。密码- 介导性MPTP增强A？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。取消CypD可持续终生保护AD患者免受A？毒性的影响 提示CypD是AD治疗药物开发的潜在靶点。然而，a CypD与AD来源的线粒体缺陷的直接联系仍然难以捉摸。目前尚不清楚CypD是否增强了 MPTP和信号转导参与AD相关的线粒体缺陷，包括线粒体的改变 形态、动力学和功能，CypD如何调节线粒体动力学，以及是否阻断CypD 挽救阿尔茨海默病线粒体损伤。为了探索与AD相关的线粒体缺陷的机制，我们 最近产生了传递线粒体细胞质杂交(Cybrid)神经元细胞系， MCI、AD和认知正常的老年配对受试者的血小板线粒体转化为线粒体DNA (MtDNA)耗尽的神经细胞。这些人类AD杂合体神经元系概括了线粒体的结构 并观察到AD患者的功能改变。我们发现CypD在MCI和AD胞质细胞中的表达增加。 重要的是，阻断CypD表达或抑制CypD活性可以恢复线粒体的形态， AD胞质细胞的动力学(融合/分裂平衡)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，改变线粒体动力学的平衡，这可能会 阿尔茨海默病相关的线粒体和突触缺陷。封锁CypD将对 线粒体和突触损伤。本项目的总体目标是对CypD在AD中的作用有新的认识 线粒体特异性缺陷及一类新的小分子CypD抑制剂的救治 线粒体和认知功能障碍。这个项目的结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，促进AD研究领域的发展。

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.