AMPK localization, expression, and activity in Alzheimer's Disease

AMPK 在阿尔茨海默病中的定位、表达和活性

• 批准号: 10537142
• 负责人: Nicholas Daniel Henkel
• 金额: $ 4.06万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537142
• 关键词: Acceleration; Address; Adenosine Monophosphate; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; American; Amyloid; Automobile Driving; Autopsy; Biochemical; Bioinformatics; Brain; Brain region; Cell Culture Techniques; Cell Nucleus; Cellular biology; Clinical; Clinical Trials; Complement; Consensus; Data; Data Set; Dementia; Disease; Disease Progression; Enzymes; Fellowship; Functional disorder; Goals; Hippocampus (Brain); Homeostasis; Human; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Literature; Measures; Mentors; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Nerve Degeneration; Neurons; Nuclear; Pathogenesis; Pathologic; Pattern; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Population; Prefrontal Cortex; Preparation; Prevalence; Protein Isoforms; Protein Kinase; Public Health; Regulation; Research; Role; Sampling; Scientist; Signal Transduction; Synapses; Techniques; Testing; Training; United States; base; career; cell type; disease phenotype; effective therapy; experience; experimental study; genetic manipulation; human old age (65+); in silico; in vivo; induced pluripotent stem cell; insight; mild cognitive impairment; novel; novel therapeutics; overexpression; pre-clinical; prospective; proteostasis; stem cells; synaptic function; tau phosphorylation; tissue processing; transcriptomics; translational physician

PROJECT SUMMARY. Alzheimer’s disease (AD) is the most common cause of dementia and it is estimated that one in ten Americans aged 65 and older has AD. The number of Americans with Alzheimer’s will escalate rapidly in coming years as the size and proportion of the U.S. population aged 65 and older increases. With no disease-altering or curative drugs available, and with more than 140 failed clinical trials, AD has become a major public health concern. There is a consensus that a deeper understanding of the pathophysiology of this devastating illness is needed to move the field forward. The amyloid-cascade hypothesis has been the leading theoretical construct guiding our understanding of the pathophysiology of AD for the past thirty years. However, this construct has overlooked the multifaceted cellular mechanisms that ultimately drive neurodegeneration and the subsequent clinical manifestations of the disease. It has been hypothesized that aberrant metabolic signaling is a major cellular mechanism driving AD. These metabolic perturbations may arise through the dysfunction of adenosine monophosphate activated protein kinase (AMPK). AMPK is the master regulator of cellular energy status. Despite its strong association with AD, AMPK has not been fully characterized in AD: it is unknown how the subcellular localization, activity, and expression are changed in vulnerable regions of the human AD brain. Pre-clinical literature implicates AMPK in the regulation of synaptic function, A metabolism, tau phosphorylation, and pathologic proteostasis in AD. AMPK is an obligatory heterotrimer composed of catalytic () and regulatory ( and ) subunits. While the  subunit has been functionally characterized in AD models, the role of the regulatory subunits is unknown. As such, a functional understanding of this kinase in human substrates is missing. The central hypothesis of this proposal is that nuclear AMPK activity and localization is decreased in AD. We will test this hypothesis by using postmortem dorsolateral prefrontal cortex and hippocampus from mild cognitive impairment and AD subjects to analyze changes of AMPK as the disease progresses (Specific Aim 1). In parallel, we will employ an omics platform to specifically complement our biochemical studies. Further, we will use cortical neurons derived from AD-patient iPSCs to evaluate the role of the overlooked regulatory AMPK1 subunit in modulating a metabolic and synaptic phenotype (Specific Aim 2). This proposal addresses a critical need to resolve the role of AMPK in the pathophysiology of this disorder. This research, in conjunction with the experienced mentoring team, will provide this prospective Fellow an excellent training experience. Specifically, this F30 Fellowship will support the applicant in gaining expertise in cell biology, bioinformatics, stem cell culture, gene-manipulation strategies, and postmortem tissue processing, in preparation for a career as a translational physician-scientist.

项目摘要。阿尔茨海默氏病（AD）是痴呆的最常见原因，估计 65岁及以上的十分之一的美国人有广告。与阿尔茨海默氏症的美国人人数将升级 在未来几年中，随着65岁及以上的美国人口的规模和比例增加。没有 可用疾病或治愈药物可用，并且有140多种临床试验，AD已成为主要的 公共卫生问题。有一个共识，即对此的病理生理有更深入的了解 需要毁灭性的疾病才能向前推进该领域。淀粉样蛋白 - cascade假设一直是领先的 理论结构指导我们过去三十年来对AD的病理生理学的理解。然而， 该构建体忽略了最终驱动神经变性和的多方面细胞机制 随后的疾病临床表现。已经假设异常的代谢信号传导 是驱动AD的主要细胞机制。这些代谢扰动可能是通过功能障碍而产生的 腺苷一磷酸激活的蛋白激酶（AMPK）。 AMPK是细胞能量的主调节器 地位。尽管AMPK与AD有很强的关联，但AMPK尚未在AD中充分表征：未知如何 在人类广告大脑的脆弱区域，亚细胞定位，活性和表达发生了变化。 临床前文献在调节突触功能，A代谢，tau磷酸化的调节中实现AMPK， 和AD中的病理蛋白抑制剂。 AMPK是一种强制性异三聚体，由催化（）和调节组成 （和）亚基。虽然亚基在AD模型中的功能表征，但 监管亚基是未知的。因此，对人类底物中这种激酶的功能理解是 丢失的。该提议的核心假设是核AMPK活性和定位减少 广告。我们将通过使用中部的后外侧前额叶皮层和海马来检验该假设 随着疾病的发展，认知障碍和AD受试者分析AMPK的变化（特定目标1）。 同时，我们将使用一个OMICS平台来特别补充我们的生化研究。此外，我们会的 使用衍生自AD患者IPSC的皮质神经元来评估被忽视的调节AMPK1的作用 调节代谢和突触表型的亚基（特定目标2）。该提议解决了一个关键 需要解决AMPK在该疾病的病理生理学中的作用。这项研究与 经验丰富的指导团队将为这位潜在的人提供出色的培训经验。具体来说， 该F30奖学金将支持申请人获得细胞生物学，生物信息学，干细胞培养的专业知识， 基因操纵策略和验尸组织加工，为作为翻译的职业做准备 医师科学家。