Role of Cyclophilin D in Abeta-induced synaptic injury

亲环蛋白 D 在 Abeta 诱导的突触损伤中的作用

基本信息

批准号：
9934321
负责人：
Shirley ShiDu Yan
金额：
$ 33.21万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-10 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9934321
关键词：
Affect Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Attenuated Binding Bioenergetics Biological Biological Assay Blood - brain barrier anatomy Blood Platelets Brain Brain Diseases Cell Death Cell Line Cell Membrane Permeability Cells Cognition Cognitive Defect Drug Kinetics Drug Targeting Equilibrium Failure Foundations Functional disorder Goals Human Hybrids Impaired cognition In Vitro Injury Learning Life Link MAPK14 gene Mediating Memory Mitochondria Mitochondrial DNA Mitochondrial Diseases Molecular Weight Morphology Mus Neuraxis Neurons Outcome Oxidative Stress Pathogenesis Pathologic Patients Peptidylprolyl Isomerase Peripheral Play Preventive Intervention Property Proteins Reactive Oxygen Species Research Respiration Role Signal Pathway Signal Transduction Silicon Structure Synapses Testing Therapeutic Agents Therapeutic Intervention Tissues Toxic effect Transgenic Mice Transgenic Organisms abeta toxicity aged base clinical application cognitive function cyclophilin D design disease phenotype drug development improved in vivo inhibitor/antagonist insight mild cognitive impairment mitochondrial dysfunction mitochondrial membrane mouse model novel overexpression preclinical evaluation prevent protective effect repaired small molecule small molecule inhibitor synaptic function therapeutic target

项目摘要

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.

线粒体和突触功能障碍是阿尔茨海默氏病（AD）受影响大脑的早期病理特征。基本的机制和修复策略尚不清楚。线粒体Aß和早期的突触线粒体缺陷。损害表明AD神经元可能会导致年度损害，这可能有助于解释您淀粉样假设的局限性。除了大脑中的Aß水平和改善认知功能外，线粒体毒品对防止至关重要和/或通过改善线粒体功能在很早的阶段停止AD。打开线粒体膜通透性孔（MPTP）导致细胞死亡的作用。介导的MPTP电位Aß和氧化应激诱导的线粒体，突触和认知功能障碍 AD鼠标模型。小鼠模型，表明CYPD是AD治疗的药物开发的潜在靶标 CYPD与广告衍生的线粒体缺陷的直接联系仍然难以捉摸。 MPTP和信号转导对与广告相关的线粒体缺陷的贡献，包括Mitchondrial的改变形态学，动力学和功能，CYPD如何调节Mitchondrial动力学以及是否阻止CYPD 营救AD Mitchondrial损伤。最近生成的多蒙蒙膜软骨细胞质杂交（Cybrid）神经元细胞与掺入来自MCI，AD和认知正常匹配的受试者的血小板线粒体进入线粒体DNA {mtDNA）耗尽的神经元细胞。在AD中观察到的功能变化。重要的是，CYPD表达或抑制CYPD活性恢复了线粒体形态，动力学（融合/裂变平衡）和功能IND Cybrid细胞。改变mitchondrial分布/形态和功能，Mitchondrial动力学的平衡，可能会基础与广告相关的Mitchondrial和突触缺陷。线粒体和突触损伤。特定的线粒体缺陷，并探索/验证一类新的小分子CYPD Inhivitor进行营救线粒体和认知功能障碍。通过确定预防和治疗干预的新目标，广告研究领域。

项目成果

期刊论文数量（30）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxidative stress-mediated activation of extracellular signal-regulated kinase contributes to mild cognitive impairment-related mitochondrial dysfunction.

DOI：
10.1016/j.freeradbiomed.2014.07.021
发表时间：
2014-10
期刊：
FREE RADICAL BIOLOGY AND MEDICINE
影响因子：
7.4
作者：
Gan, Xueqi;Wu, Long;Huang, Shengbin;Zhong, Changjia;Shi, Honglian;Li, Guangyue;Yu, Haiyang;Swerdlow, Russell Howard;Chen, John Xi;Yan, Shirley ShiDu
通讯作者：
Yan, Shirley ShiDu

High Dietary Advanced Glycation End Products Impair Mitochondrial and Cognitive Function.