Nutrient-Induced Mitochondrial Activity (NiMA): A Novel Lysosome to Mitochondria Signaling Pathway, its mechanisms and role in Alzheimer's Disease

营养诱导的线粒体活性（NiMA）：一种新型溶酶体至线粒体信号通路、其机制及其在阿尔茨海默病中的作用

• 批准号: 10602457
• 负责人: Andres M Norambuena
• 金额: $ 70.11万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602457
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Amino Acids; Amyloid beta-Protein Precursor; Animals; Autophagocytosis; Biological Assay; Biological Markers; Biological Process; Brain; Caloric Restriction; Cell Cycle; Cell Respiration; Cell membrane; Cell model; Cell physiology; Cellular biology; Collection; Communication; Complex; Deterioration; Development; Disease; Disease Progression; Early Diagnosis; Early treatment; Energy Metabolism; Environment; Experimental Designs; FRAP1 gene; Fluorescence; Functional disorder; Hormones; Human; Human Amyloid Precursor Protein; Human Development; Impaired cognition; Impairment; In Vitro; Insulin; Insulin Resistance; Intake; Interruption; Iowa; Libraries; Link; London; Lysosomes; Malignant Neoplasms; Mediating; Metabolic Diseases; Metabolic dysfunction; Metabolism; Microscopy; Mitochondria; Modeling; Molecular; Mus; Mutation; Neurodegenerative Disorders; Neurons; Nicotinamide adenine dinucleotide; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Organelles; Oxygen; Palliative Care; Pathogenesis; Pathologic; Pathway interactions; Persons; Phosphotransferases; Play; Probability; Production; Protein Biosynthesis; Protein Kinase; Provider; Regulation; Research; Role; Signal Pathway; Signal Transduction; Swedish mutation; Testing; Tg2576; Time; Tissues; Toxic effect; United States; Work; abeta accumulation; abeta oligomer; age related; brain cell; cofactor; detection of nutrient; familial Alzheimer disease; fatty acid transport; fluorescence lifetime imaging; human disease; improved; in vivo; interest; kinase inhibitor; mRNA Translation; metabolic imaging; mitochondrial dysfunction; mitochondrial metabolism; mouse model; neuron loss; novel; novel therapeutic intervention; novel therapeutics; protein complex; scaffold; screening; successful intervention; tau Proteins; tau aggregation; tau dysfunction; tau interaction; two-photon

Alzheimer’s disease (AD) is an aging-related neurodegenerative disorder that affects ~5.8 million people in the United States. Despite intensive research efforts in recent decades, neither an effective palliative treatment nor a cure is available, largely due to our limited understanding of the molecular mechanisms that are disrupted in this devastating disease. Current research suggests that the gradual cognitive decline in AD occurs by the concurrent deleterious action of soluble amyloid-beta (Aβ) oligomers (AβOs) and intracellular tau in the brain. Emerging evidence, however, suggests that development of AD may also be attributed to a progressive deterioration of mitochondrial functioning in brain cells, especially neurons. Besides, AD development has recently been linked to a progressive impairment in brain’s ability to respond to hormones such as insulin—a condition known as brain insulin resistance. To investigate these emerging but still elusive molecular mechanisms of AD, we ask the question: is there any connection between AβOs accumulation, tau, compromised mitochondrial energy metabolism, and increased insulin resistance in the AD brain and if so, how? It is known that AβOs interact with the neuronal plasma membrane, which may interrupt communications between neurons and their environment and disrupt their normal functions. We are particularly interested in how the AβOs disrupts neuron’s ability to properly respond to the presence of insulin or nutrients and how it affects ATP production and other mitochondrial functions. Along this direction, we recently discovered Nutrient-Induced Mitochondrial Activity (NiMA), a novel communication pathway between the lysosome and mitochondria, which is mediated by the lysosome-associated mechanistic target of rapamycin complex 1 (mTORC1). Interestingly, the abnormal accumulation of AβOs in AD cellular models disrupted NiMA in a tau-dependent manner. In this project, we aim to elucidate molecular mechanisms mediating NiMA and to understand how this pathway is disrupted by AβOs and tau in AD, by screening regulator of this pathway in human neurons in culture and using two-photon fluorescence lifetime imaging microscopy and state-of-the-art mitochondrial and metabolic imaging of the mouse brain in vivo. Successful completion of this project not only will advance our understanding of these earliest steps occurred in AD progression, but also may lead to new therapeutic strategies that could help us cure this disease.

阿尔茨海默病（AD）是一种与衰老相关的神经退行性疾病，影响约580万人， 美国的尽管近几十年来进行了深入的研究，但无论是有效的姑息治疗还是 治疗是可行的，主要是由于我们对破坏的分子机制的理解有限， 这种毁灭性的疾病。目前的研究表明，AD患者的认知能力逐渐下降是由 可溶性淀粉样蛋白-β（Aβ）寡聚体（AβOs）和脑中细胞内tau蛋白的并发有害作用。 然而，新出现的证据表明，AD的发展也可能归因于进行性的 脑细胞中线粒体功能的退化，尤其是神经元。此外，AD开发 最近被认为与大脑对胰岛素-a等激素反应能力的进行性损伤有关。 这种情况被称为脑胰岛素抵抗。为了研究这些新出现但仍然难以捉摸的分子 AD的机制，我们提出了一个问题：AβOs积累，tau， 损害线粒体能量代谢，增加AD大脑中的胰岛素抵抗，如果是这样，如何？ 已知AβOs与神经元质膜相互作用，这可能会中断通信 神经元和环境之间的联系，破坏它们的正常功能。我们特别感兴趣的是 Aβ O破坏了神经元对胰岛素或营养物质的存在做出适当反应的能力， ATP生产和其他线粒体功能。沿着这个方向，我们最近发现了营养诱导 线粒体活性（NiMA）是溶酶体和线粒体之间的一种新的通讯途径， 由雷帕霉素复合物1（mTORC 1）的溶酶体相关机制靶点介导。有趣的是， AD细胞模型中Aβ O的异常积聚以tau依赖性方式破坏NiMA。在这 项目，我们的目标是阐明介导NiMA的分子机制，并了解这一途径是如何 通过在培养的人神经元中筛选该途径的调节剂， 双光子荧光寿命成像显微镜和最先进的线粒体和代谢成像 小鼠大脑的活体组织。这个项目的成功完成不仅将促进我们对这些问题的理解， 最早的步骤发生在AD进展中，但也可能导致新的治疗策略，可以帮助我们 治好这个病。