Mitochondrial pore and synaptic stress in Alzheimer's disease

阿尔茨海默病中的线粒体孔和突触应激

基本信息

批准号：
8850761
负责人：
Heng Du
金额：
$ 24.15万
依托单位：
UNIVERSITY OF TEXAS DALLAS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850761
关键词：
AD transgenic mice Address Age Alzheimer&apos s Disease Animals Attenuated Axon Biological Assay Calcium Defect Dendritic Spines Development Energy Metabolism Environment Foundations Generations Genetic Hippocampus (Brain)Learning Maintenance Mediating Membrane Membrane Potentials Memory Mentors Mitochondria Mitochondrial Swelling Morphology Mus Neurons Oxidative Stress Oxygen Consumption Pathogenesis Pathology Permeability Play Principal Investigator Property Proteins Research Resistance Respiration Role Stress Synapses Synaptic Transmission Testing Transgenic Mice Vertebral column abstracting base career cell motility cyclophilin D density enzyme activity insight mitochondrial dysfunction mitochondrial membrane mitochondrial permeability transition pore mouse model novel novel therapeutic intervention overexpression programs response synaptic failure synaptic function trafficking

项目摘要

Program Director/Principal Investigator: Du, Heng Project Description/Abstract Mitochondrial dysfunction and synaptic loss are early pathological features of Alzheimer's disease. Recent studies indicate that mitochondrial alterations in AD underlie A¿-mediated synaptic pathology as evidenced by the observations: 1) significant correlation of mitochondrial dysfunction with synaptic loss in AD; and 2) the protection of mitochondria attenuates A¿-induced synaptic changes. However, the mechanisms of A¿-induced mitochondrial dysfunction and the consequent synaptic damages have not fully delineated. Notably, mitochondria in neurons are heterogeneous in their properties. A sub-group of neuronal mitochondria locating at synapses or namely synaptic mitochondria play a pivotal role in maintaining synaptic activity/function due to their physical proximity to synapses. Thus, to elucidate the mechanisms underlying A¿-potentiated synaptic mitochondrial dysfunction is of great significance to deepen our understanding of the synaptic pathology in the pathogenesis of the AD. In the preliminary studies, we have demonstrated that synaptic mitochondria undergo increased propensity towards cyclophilin D (cypD)-mediated mitochondrial permeability transition pore (mPTP) in the A¿ milieu, transgenic AD mice overexpressing A¿. Along with these changes, A¿-insulted synaptic mitochondria underwent respiration defects. In addition, A¿ treatment resulted in decreased axonal mitochondrial density and the loss of synapses in cultured hippocampal neurons. As a contrast, these detrimental effects on synaptic mitochondrial and synaptic alterations were significantly attenuated by the blockade of cypD through genetic depletion of cypD.Thus, I have formulated a hypothesis that cypD-mediated mPTP is a potential mechanism underlying A¿-induced synaptic mitochondrial dysfunction and synaptic alterations. To address this concept, I will utilize an AD mouse model (APP mice) and a novel genetically manipulated transgenic mouse model (genetic cypD-deficient APP mice) as well as cypD-deficiency hippocampal neuron cultures for the studies proposed in this application. This project contains three aims: 1). to determine the impact of cypD-mediated mPTP on synaptic mitochondrial function in APP mice; 2) to determine the impact of cypD-mediated mPTP on synaptic (axonal) mitochondrial dynamics and motility in A¿ milieus; and 3) to determine whether cypD-mediated synaptic mitochondrial dysfunction contributes to A¿-induced synaptic alterations in APP mice. Upon the completion of this project, I will determine the involvement of cypD mediated mPTP in A¿ induced synaptic mitochondrial dysfunction, and the impact of cypD mediated mPTP on synaptic mitochondrial dynamics and motility, and synaptic function as well as animal learning/memory ability in APP/A¿ overexpressing mice. Finding derived from this study will have positive impact on the development of new therapeutic approaches for AD treatment. This project will also serve as a firm foundation of my scientific career to establish a research direction distinct from my mentors' by the combination of synaptic mitochondrial dysfunction and synaptic alterations in AD. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

项目主任/首席研究员：杜恒项目描述/摘要线粒体功能障碍和突触丧失是阿尔茨海默病的早期病理特征。最近的研究表明 AD 中的线粒体改变是 A¿ -介导的突触病理学为观察结果证明：1）AD 中线粒体功能障碍与突触丧失显着相关； 2) 线粒体的保护会减弱 A¿然而，引起突触变化的机制。一个值得注意的是，诱导的线粒体功能障碍和随之而来的突触损伤尚未完全阐明。神经元中的线粒体具有异质性，位于神经元线粒体的一个亚组中。突触或即突触线粒体在维持突触活动/功能中发挥着至关重要的作用，因为它们因此，为了阐明 A¿ 的机制。 - 增强突触线粒体功能障碍对于加深我们对突触病理学的认识具有重要意义在初步研究中，我们已经证明突触线粒体经历了 AD 的发病机制。亲环蛋白 D (cypD) 介导的线粒体通透性转换孔 (mPTP) 的倾向增加在A??环境，过度表达 A 的转基因 AD 小鼠随着这些变化，A¿ - 侮辱突触此外，线粒体还存在呼吸缺陷。治疗导致轴突减少相比之下，这些是在培养的海马神经元中线粒体密度和突触损失。对突触线粒体和突触改变的不健康影响被显着减弱通过 cypD 的基因耗竭来阻断 cypD。因此，我提出了一个假设，即 cypD 介导的 mPTP 是 A¿ 的潜在机制-诱导突触线粒体功能障碍和突触为了解决这个概念，我将利用 AD 小鼠模型（APP 小鼠）和一种新的基因。操纵转基因小鼠模型（遗传性 cypD 缺陷型 APP 小鼠）以及 cypD 缺陷型本申请提出的研究的海马神经元培养物包含三个目标：1)。确定 cypD 介导的 mPTP 对 APP 小鼠突触线粒体功能的影响 2) 确定 cypD 介导的 mPTP 对 A¿ 突触（轴突）线粒体动力学和运动的影响环境；和 3) 确定cypD介导的突触线粒体功能障碍是否导致A¿诱导突触该项目完成后，我将确定 cypD 介导的参与。 A 中的 mPTP诱导的突触线粒体功能障碍以及 cypD 介导的 mPTP 对突触的影响 APP/A 中的线粒体动力学和运动性、突触功能以及动物学习/记忆能力这项研究的发现将对新小鼠的开发产生积极影响。该项目也将为我的科学生涯奠定坚实的基础。通过突触线粒体的结合，建立一个不同于导师的研究方向 AD 中的功能障碍和突触改变。 PHS 398/2590（修订版 06/09）页面延续格式页面

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of succinyl-CoA synthase ADP-forming β subunit disrupts mtDNA stability and mitochondrial dynamics in neurons.

琥珀酰 CoA 合酶 ADP 形成 β 亚基的丢失会破坏神经元中 mtDNA 的稳定性和线粒体动力学。

DOI：
发表时间：
2017-08-02
期刊：
影响因子：
4.6
作者：
Zhao, Yujun;Tian, Jing;Sui, Shaomei;Yuan, Xiaodong;Chen, Hao;Qu, Chuanqiang;Du, Yifeng;Guo, Lan;Du, Heng
通讯作者：
Du, Heng

Synaptosomal Mitochondrial Dysfunction in 5xFAD Mouse Model of Alzheimer's Disease.

阿尔茨海默病 5xFAD 小鼠模型中的突触体线粒体功能障碍。

DOI：
发表时间：
2016
期刊：
影响因子：
3.7
作者：
Wang, Lu;Guo, Lan;Lu, Lin;Sun, Huili;Shao, Muming;Beck, Simon J;Li, Lin;Ramachandran, Janani;Du, Yifeng;Du, Heng
通讯作者：
Du, Heng

Antioxidant Treatment in Male Mice Prevents Mitochondrial and Synaptic Changes in an NMDA Receptor Dysfunction Model of Schizophrenia.

雄性小鼠的抗氧化治疗可预防精神分裂症 NMDA 受体功能障碍模型中的线粒体和突触变化。

DOI：
发表时间：
2017-07
期刊：
影响因子：
3.4
作者：
Phensy, Aarron;Driskill, Christopher;Lindquist, Karen;Guo, Lan;Jeevakumar, Vivek;Fowler, Bryan;Du, Heng;Kroener, Sven
通讯作者：
Kroener, Sven

Transient Cerebral Ischemia Promotes Brain Mitochondrial Dysfunction and Exacerbates Cognitive Impairments in Young 5xFAD Mice.

短暂性脑缺血会促进年轻 5xFAD 小鼠的大脑线粒体功能障碍并加剧认知障碍。

DOI：
发表时间：
2015
期刊：
影响因子：
3.7
作者：
Lu, Lin;Guo, Lan;Gauba, Esha;Tian, Jing;Wang, Lu;Tandon, Neha;Shankar, Malini;Beck, Simon J;Du, Yifeng;Du, Heng
通讯作者：
Du, Heng

Cyclophilin D regulates neuronal activity-induced filopodiagenesis by fine-tuning dendritic mitochondrial calcium dynamics.

Cyclophilin D 通过微调树突状线粒体钙动力学来调节神经元活动诱导的丝状伪足形成。