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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：
9533434
负责人：
Shirley ShiDu Yan
金额：
$ 51.56万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
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 2019-05-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9533434
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该病的早期病理特征阿尔茨海默病（AD）影响大脑。 Aβ 对线粒体和突触功能障碍。挽救此类损伤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 发病机制中的作用。线粒体 Aβ 的积累可能是导致线粒体和神经元扰动。 TOMM40（外线粒体转位酶 Membrane-40kD) 是 TOM 复合物的关键亚基，是大量物质的主要进入通道。大多数输入的蛋白质必须通过才能进入线粒体内部。多态性 inTOMM40 与迟发性 AD 风险增加和认知能力下降相关性能48.该多态性是遗传中唯一鉴定的核编码基因迄今为止的研究可能会导致 LOAD 相关的线粒体功能障碍。 Aβ 和 APP可以通过体外细胞中的TOMM40通道导入线粒体然而，TOMM40 介导的 Aβ 导入机制仍不清楚，其影响 TOMM40 对淀粉样蛋白病理学、线粒体和突触变性的影响，以及 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 敲除小鼠的线粒体 Aβ 水平显着降低，过表达 Aβ 的 Tg mAPP 小鼠线粒体和突触功能得到改善。此外，Tg mAPP 小鼠中 TOMM40 水平降低会减弱先天免疫和促炎症反应。这些数据表明 TOMM40 可能具有潜在的重要性 AD 线粒体淀粉样蛋白病理学。我们假设 TOMM40 的功能受损导致与淀粉样蛋白病理学相关的慢性线粒体 Aβ 积累 AD，导致线粒体和突触变性。该提案的目标是获得关于 TOMM40 在 AD 发病机制中作用的新见解，重点关注线粒体 Aβ 积累/清除、淀粉样蛋白病理学、突触线粒体特性、氧化应激、炎症和突触功能，利用新型基因操纵转基因 TOMM40/AD 小鼠模型和 TOMM40 水平改变的神经元培养（增加/减少）在富含 Aβ 的环境中（整体和神经元 TOMM40 遗传缺陷以及增加 AD 型转基因小鼠中过表达 Aβ 的神经元 TOMM40）。项目成果可能表明 TOMM40 可能是限制性的潜在新治疗靶点线粒体淀粉样蛋白病理学从而阻止 AD 进展。