Regulation of CHCHD6 in Alzheimer's disease

CHCHD6 在阿尔茨海默病中的调控

• 批准号: 10461551
• 负责人: XIN QI
• 金额: $ 213.6万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461551
• 关键词: AD transgenic mice; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autopsy; Behavioral; Biochemical; Bioenergetics; Biological Assay; Brain; Cell Culture Techniques; Cell Nucleus; Cell Survival; Cells; Cholesterol; Cholesterol Homeostasis; Chronic; Cognitive; Cognitive deficits; Complex; Crista ampullaris; Defect; Dementia; Dependovirus; Deposition; Development; Disease Progression; Exposure to; Failure; Financial compensation; Genetic Transcription; Hippocampus (Brain); Homeostasis; Impairment; Knock-in; Knock-in Mouse; Light; Link; Lipids; Measures; Mediating; Membrane; Messenger RNA; Metabolic; Mitochondria; Mitochondrial Proteins; Molecular; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptides; Physiological; Play; Population; Process; Proteins; Proteomics; Regulation; Research; Respiration; Risk Factors; Role; Sampling; Signal Pathway; Signal Transduction; Site; Sterols; Stress; Symptoms; Synapses; System; Therapeutic; Viral; age related; amyloid pathology; density; effective therapy; improved; in vivo; induced pluripotent stem cell; knock-down; loss of function; mitochondrial dysfunction; mouse model; neuronal survival; neuropathology; novel; overexpression; protein metabolism; transcriptome sequencing; validation studies

PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia, affecting ~10% of the population over 65. Processing amyloid-beta precursor protein (APP) into amyloid-beta peptide (Aβ) is an important and fundamental aspect of AD pathogenesis. However, the signaling pathways that control this process are not well defined. Mitochondrial dysfunction is a prominent early feature in susceptible neurons in the brain of patients with AD and plays a critical role in AD pathogenesis. APP and its metabolic fragments are known to localize to mitochondria where they negatively influence mitochondrial function. Conversely, neurons with impaired mitochondrial function and bioenergetics also contribute to APP processing and synaptic loss. Although evidence suggests that APP-mitochondrial interactions are important for the cognitive deficits and amyloid genesis in AD, the field lacks a detailed understanding of the mechanisms that coordinate APP processing and functional mitochondrial deficiency. The coiled-coil-helix-coiled-coil-helix domain-containing protein 6 (CHCHD6) is an evolutionarily conserved nucleus-encoded mitochondrial protein. CHCHD6 is a core component of the mitochondrial contact site and cristae organization system (MICOS), which controls mitochondrial respiration and redox regulation, lipid homeostasis, and membrane ultrastructure and dynamics. Recent proteomics studies have shown a decrease in CHCHD6 in brain samples of AD patients and AD mice. However, the role of CHCHD6 in AD pathology is unknown. Our preliminary studies have revealed a previously unidentified role of CHCHD6 in the regulation of APP-mediated neuropathology and cognitive deficiency. The objective of this application is to determine the role of CHCHD6-mediated AD pathology at both mechanistic and therapeutic levels. In Aim 1, we will determine the causes and consequences of CHCHD6 loss of function in AD models. In Aim 2, we will dissect the mechanism of CHCHD6 loss in AD pathology. In Aim 3, we will determine whether compensation for the loss of CHCHD6 in AD mice alleviates neuropathology and cognitive deficits. If successful, these studies will establish CHCHD6 as a key molecule linking APP processing, lipid disturbance, and mitochondrial dysfunction and advance our understanding of AD pathology. The findings generated by this project will also have a significant impact on AD research by identifying CHCHD6 as a novel target for limiting mitochondrial dysfunction, amyloid pathology, and cognitive deficits in AD.

项目摘要 阿尔茨海默病（AD）是痴呆症的最常见形式，影响超过10%的人口。 65.将淀粉样β前体蛋白（APP）加工成淀粉样β肽（Aβ）是一种重要的， AD发病机制的基本方面。然而，控制这一过程的信号通路并不 定义明确。线粒体功能障碍是脑内易感神经元的一个突出的早期特征， 在AD的发病机制中起着关键作用。已知APP及其代谢片段 定位于线粒体，在那里它们对线粒体功能产生负面影响。相反， 受损的线粒体功能和生物能量学也有助于APP加工和突触损失。 尽管有证据表明APP-线粒体相互作用对认知缺陷和 由于淀粉样蛋白在AD中的发生，该领域缺乏对协调APP的机制的详细了解 加工和功能性线粒体缺陷。所述含有卷曲螺旋结构域的卷曲螺旋结构域 蛋白6（CHCHD 6）是进化上保守的核编码线粒体蛋白。CHCHD 6是一个核心 线粒体接触位点和嵴组织系统（MICOS）的组成部分，控制 线粒体呼吸和氧化还原调节，脂质稳态和膜超微结构和动力学。 最近的蛋白质组学研究表明，AD患者和AD小鼠的脑样品中CHCHD 6减少。 然而，CHCHD 6在AD病理学中的作用尚不清楚。我们的初步研究显示 CHCHD 6在APP介导的神经病理学和认知功能调节中的作用尚未确定 缺陷本申请的目的是确定CHCHD 6介导的AD病理学在两种疾病中的作用。 机制和治疗水平。在目标1中，我们将确定CHCHD的原因和后果6 AD模型中的功能丧失。在目标2中，我们将剖析AD病理学中CHCHD 6丢失的机制。在 目的3，我们将确定AD小鼠中CHCHD 6缺失的补偿是否会加重神经病理学 和认知缺陷如果成功，这些研究将确立CHCHD 6作为连接APP的关键分子。 加工，脂质紊乱和线粒体功能障碍，并推进我们对AD病理学的理解。 该项目产生的结果也将对AD研究产生重大影响， CHCHD 6作为限制线粒体功能障碍、淀粉样病变和认知缺陷的新靶点 AD.