Interplay between amyloid precursor protein metabolism and ER-mitochondria contact

淀粉样蛋白前体蛋白代谢与内质网线粒体接触之间的相互作用

• 批准号: 10470218
• 负责人: Bingwei Lu
• 金额: $ 19.68万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470218
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyotrophic Lateral Sclerosis; Apoptosis; Autophagocytosis; Behavioral; Biochemical; Bioenergetics; Biology; Brain; Brain Diseases; Buffers; C-terminal; Cells; Cellular Structures; Citric Acid Cycle; Clinical Trials; Complex; DNA Sequence Alteration; Defect; Degenerative Disorder; Dementia; Development; Differentiation and Growth; Disease; Drosophila genus; Elderly; Electron Transport; Enzymes; Etiology; Exhibits; Failure; Foundations; Functional disorder; Future; Genetic; Genetic study; Goals; Health; Homeostasis; Human; Human Genetics; Image; Impairment; Lead; Link; Mammalian Cell; Mediating; Metabolism; Mitochondria; Modeling; Morphogenesis; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Organelles; Output; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Patients; Pharmacologic Substance; Pharmacology; Physiological; Physiology; Positioning Attribute; Process; Production; Proteins; Public Health; Regulation; Research; Role; Senile Plaques; Signal Transduction; Site; Structure; Synapses; Synaptic plasticity; Testing; Whole Organism; amyloid formation; disease phenotype; effective therapy; extracellular; familial Alzheimer disease; fly; human old age (65+); in vivo; mitochondrial dysfunction; novel; novel therapeutic intervention; presenilin; protein function; protein metabolism; trafficking; transmission process; uptake

Alzheimer's disease (AD) remains a looming public health crisis, despite intensive research and pharmaceutical development efforts. No effective treatment option is currently available that can halt the disease process. The recent failures of high-profile clinical trials targeting the amyloid plaques and neurofibrillary tangles, the pathological hallmarks of the AD identified by Dr. Alois Alzheimer more than a century ago and the focus of extensive research and pharmaceutical development efforts, suggest that new directions in delineating the pathogenic mechanisms of AD are warranted before effective treatment of the disease can be achieved. Mitochondria are dynamic and complex organelles with essential roles in many aspects of biology, from energy production and intermediary metabolism to intracellular signaling and apoptosis. These broad functions position mitochondrion as a central player in human health. In neurons, mitochondria and synapses are intimately linked. In addition to the central role of mitochondria in bioenergetics, they are also critically important for maintaining cellular Ca2+ homeostasis. Ca2+ uptake by mitochondria helps buffer cytosolic Ca2+ transients arising from neuronal activation, protecting against the detrimental effects of bursts of Ca2+ influx. Under basal conditions, Ca2+ entry into mitochondria is needed for normal neuronal physiology. The ER- mitochondria contact site (ERMCS) are recognized as key cellular structures regulating mito-Ca2+ homeostasis. Moreover, there is an emerging recognition of ERMCS impairment in neurodegenerative diseases including AD. How ERMCS and mito-Ca2+ homeostasis are altered, and their contribution to disease phenotypes in in vivo settings, however, are not well understood. The goal of this proposal is to test the central hypothesis that an interplay between APP metabolism and ERMCS directs ER-mitochondrial Ca2+ signaling, and that defects in this process contributes to the etiology of AD. To test this hypothesis, we propose to achieve the following Specific Aims in this exploratory project: Aim 1. Examine defects in ERMCS formation in a Drosophila AD model and AD patient derived cells; Aim 2. Test the roles of ERMCS proteins that direct mito-Ca2+ homeostasis in mediating APP function in disease pathogenesis. By providing evidence for the involvement of ERMCS and mito-Ca2+ in APP function at the organellar, synaptic, and organismal levels, these studies will lay the foundation for future studies addressing the regulation and function of ERMCS in normal brain physiology, which will significantly advance our understanding of the fundamental roles of mitochondria and Ca2+ signaling in AD and ultimately offer novel therapeutic strategies.

尽管进行了深入的研究和 制药开发工作。目前尚无有效的治疗选项可以阻止 疾病过程。针对淀粉样斑块和 神经原纤维缠结，Alois Alzheimer博士确定的广告的病理标志，而不是一个 世纪前以及广泛的研究和药物开发工作的重点，表明了新的 在有效治疗之前，必须使用描述AD的致病机制的方向 可以实现疾病。 线粒体是动态且复杂的细胞器，在生物学的许多方面具有重要作用， 能源生产和中介代谢细胞内信号传导和凋亡。这些广泛的功能 将线粒体定位为人类健康的中心参与者。在神经元中，线粒体和突触是 密切联系。除了线粒体在生物能力中的核心作用外，它们还至关重要 对于维持细胞Ca2+稳态至关重要。线粒体的Ca2+摄取有助于缓冲胞质Ca2+ 神经元激活产生的瞬态，可抵御Ca2+流入爆发的有害影响。 在基础条件下，正常神经元生理学需要Ca2+进入线粒体。 ER- 线粒体接触位点（ERMC）被认为是调节线粒体CA2+稳态的关键细胞结构。 此外，人们对神经退行性疾病中的ERMC损害有一种新兴的认识 广告。 ERMC和MITO-CA2+稳态如何改变，它们对疾病表型的贡献 但是，体内设置尚不清楚。该提议的目的是检验中心假设 APP代谢与ERMC之间的相互作用指导ER-Mitochrial Ca2+信号传导，并且缺陷在 这个过程有助于AD的病因。为了检验这一假设，我们建议实现以下 这个探索性项目的具体目的：目标1。检查果蝇广告中ERMC形成中的缺陷 模型和AD患者衍生的细胞； AIM 2。测试引导MITO-CA2+稳态的ERMCS蛋白的作用 在介导疾病发病机理中的APP功能中。通过提供ERMC和ERMC参与的证据 Mito-Ca2+在细胞器，突触和生物水平的APP功能中，这些研究将奠定 未来研究的基础，涉及ERMC在正常脑生理学中的调节和功能， 这将大大提高我们对线粒体和CA2+信号的基本作用的理解 在广告中，最终提供新颖的治疗策略。