Saturday, November 23, 2024
11/23/2024
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 AMPK1 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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
