TOMM40-mediated mitochondrial dysfunction and Alzheimers disease

TOMM40介导的线粒体功能障碍和阿尔茨海默病

基本信息

批准号：
9934323
负责人：
Shirley ShiDu Yan
金额：
$ 55.64万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9934323
关键词：
Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Attenuated Behavioral Brain Cell Culture Techniques Cells Chronic Cognition Cognitive Complex Data Disease Progression Environment Event Family Functional disorder Genes Genetic Genetic Polymorphism Genetic study Goals Human Immune Impairment In Vitro Inflammasome Inflammation Injury Late Onset Alzheimer Disease Learning Maintenance Mediating Mediator of activation protein Memory impairment Mitochondria Mitochondrial DNA Molecular Mus Natural Immunity Neurons Nuclear Outcome Outer Mitochondrial Membrane Oxidative Stress Pathogenesis Pathologic Pathology Pattern Pattern recognition receptor Pilot Projects Positioning Attribute Preventive Intervention Production Property Protein Import Research Risk Role Synapses Synaptic Transmission Synaptic plasticity Therapeutic Agents Therapeutic Intervention Transcriptional Activation Transgenic Mice Transgenic Organisms Validation amyloid pathology chemokine cytokine drug development improved insight knock-down marenostrin mitochondrial dysfunction mouse model neuroinflammation new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression protective effect receptor receptor for advanced glycation endproducts response synaptic function transcription factor translocase

项目摘要

Summary Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer's disease (AD) affected brain. Aβ has deleterious effects on mitochondrial and synaptic dysfunction. The underlying mechanisms and strategies to rescue such injury remain unclear. Recent studies have highlighted the role of mitochondrial Aβ in AD pathogenesis. Accumulation of mitochondrial Aβ may be an initiating pathological event leading to mitochondrial and neuronal perturbation. TOMM40 (Translocase of the Outer Mitochondrial Membrane-40kD) is the key subunit of the TOM complex, the main entry channel for the vast majority of imported proteins must pass to enter the mitochondrial interior. A polymorphism inTOMM40 is associated with an increased risk of late-onset AD and decreased cognitive performance48. This polymorphism is the only nuclear-encoded gene identified in genetic studies to date that presumably contributes to LOAD-related mitochondrial dysfunction. Aβ and APP can be imported into the mitochondria through the TOMM40 channel in an in vitro cell culture, however, the TOMM40-mediated Aβ import mechanism remains unclear and the impact of TOMM40 on amyloid pathology, mitochondrial and synaptic degeneration, and neuroinflammation in Aβ milieu have not yet been elucidated. In our pilot studies, we observed that TOMM40 knockdown mice displayed significantly reduced mitochondrial Aβ levels, along with improvement in mitochondrial and synaptic function in Tg mAPP mice overexpressing Aβ. Furthermore, reduced TOMM40 levels in Tg mAPP mice attenuate the innate immune and proinflammatory response. These data suggest that TOMM40 may potentially be of importance in mitochondrial amyloid pathology of AD. We hypothesize that impaired function of TOMM40 contributes to chronic mitochondrial Aβ accumulation relevant to developing amyloid pathology of AD, leading to mitochondrial and synaptic degeneration. The goal of this proposal is to gain new insight into the role of TOMM40 in AD pathogenesis, focusing on mitochondrial Aβ accumulation/clearance, amyloid pathology, synaptic mitochondrial properties, oxidative stress, inflammation, and synaptic function, utilizing a novel genetically manipulated transgenic TOMM40/AD mouse models and neuronal culture with altered TOMM40 levels (gaining/losing) in an Aβ-rich environment (genetic deficiency of global and neuronal TOMM40 and increased neuronal TOMM40 in AD-type transgenic mice overexpressing Aβ). The outcomes of the project could present that TOMM40 might be a potential new therapeutic target for limiting mitochondrial amyloid pathology thereby halting AD progression.

概括线粒体功能障碍和突触损伤是早期病理特征阿尔茨海默氏病（AD）影响了大脑。 Aβ已删除对线粒体和突触功能障碍。挽救这种伤害的基本机制和策略仍然存在不清楚。最近的研究强调了线粒体Aβ在AD发病机理中的作用。线粒体Aβ的积累可能是一个引发病理事件，导致线粒体和神经元扰动。 Tomm40（外部线粒体的易位酶）膜40KD）是Tom Complex的关键亚基，Tom Complex是疫苗的主要入口通道大多数进口蛋白必须通过才能进入线粒体内部。多态性 Intomm40与迟发广告的风险增加并改善认知有关性能48。该多态性是唯一在通用中鉴定的核编码基因迄今为止，可能导致与负荷相关的线粒体功能障碍的研究。 Aβ和可以在体外细胞中通过Tomm40通道导入APP 然而，培养物TOMM40介导的Aβ进口机制尚不清楚，影响 TOMM40关于淀粉样病理学，线粒体和突触变性的 Aβ环境中的神经炎症尚未阐明。在我们的试点研究中，我们观察到 Tomm40敲低的小鼠沿着线粒体Aβ水平显着降低随着过表达Aβ的TG MAPP小鼠的线粒体和突触功能的改善。此外，TG MAPP小鼠的TOMM40水平降低，减轻了先天免疫和促炎反应。这些数据表明Tomm40可能很重要在AD的线粒体淀粉样病理学中。我们假设Tomm40的功能受损有助于与发展淀粉样病理学有关的慢性线粒体Aβ积累 AD，导致线粒体和突触变性。该提议的目的是获取对Tomm40在AD发病机理中的作用的新见解，重点是线粒体Aβ 积累/清除，淀粉样病理学，突触线粒体特性，氧化应激，炎症和突触功能，使用一种新型的遗传操纵转基因 TOMM40/AD小鼠模型和神经元培养，Tomm40水平改变（获得/失去）在富含Aβ的环境中（全球和神经元Tomm40的遗传缺乏并增加过表达Aβ的AD型转基因小鼠中的神经元TOMM40。项目的结果可能表明Tomm40可能是限制的潜在新治疗靶点线粒体淀粉样病理学，从而停止AD进展。