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.

阿尔茨海默氏病（AD）是一种与衰老有关的神经退行性疾病，影响约580万人 美国。尽管最近几十年进行了深入的研究工作，但既不是有效的姑息治疗，也不是 可以治愈，这在很大程度上是由于我们对被破坏的分子机制的理解有限 这种毁灭性的疾病。当前的研究表明，AD的年级认知下降是由 固体淀粉样β（Aβ）低聚物（AβOS）和大脑内细胞内TAU的同时有害作用。 但是，新兴的证据表明，AD的发展也可能归因于进步性 脑细胞，尤其是神经元中线粒体功能的恶化。此外，广告开发有 最近，与大脑对胰岛素等激素反应能力的渐进障碍有关 - 条件称为脑胰岛素抵抗。研究这些新兴但仍然难以捉摸的分子 AD的机制，我们提出一个问题：AβOS积累，tau，是否有任何联系 线粒体能量代谢受损，并增加了AD大脑中的胰岛素抵抗，如果是，如何？ 众所周知，AβOS与神经元质膜相互作用，这可能中断通信 在神经元和环境之间，破坏其正常功能。我们对如何 AβOS破坏了神经元正确反应胰岛素或营养的能力，以及它如何影响 ATP产生和其他线粒体功能。沿着这个方向，我们最近发现了营养诱导的 线粒体活性（NIMA），这是一种溶酶体和线粒体之间的新型通信途径， 由雷帕霉素复合物1（MTORC1）的溶酶体相关机械靶标介导。有趣的是， AD细胞模型中AβOS的异常积累以Tau依赖性方式破坏了NIMA。在这个 项目，我们旨在阐明介导NIMA的分子机制，并了解该途径的方式 通过筛选培养物中人类神经元中该途径的调节剂在AD中被AβOS和TAU破坏，并使用 两光子荧光寿命成像显微镜以及最先进的线粒体和代谢成像 体内小鼠脑的成功完成该项目不仅会促进我们对这些项目的理解 最早的步骤发生在广告进展中，但也可能导致新的治疗策略，可以帮助我们 治愈这种疾病。