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.

项目总结。据估计，阿尔茨海默病（AD）是痴呆症最常见的原因