Alzheimer?s disease (AD) is the most common form of dementia in the elderly, and may become a new epidemic in the 21st century in accordance with the rapid growth of the aging population. There is currently no known cure or treatment to stop the progression of AD. Moreover, the basic molecular mechanisms responsible for AD remain elusive. Two key events in AD pathophysiology are impaired capacity of de novo protein synthesis (mRNA translation) and disrupted cellular energy homeostasis. AMP-activated protein kinase (AMPK) acts as a central cellular energy sensor to maintain cellular energy homeostasis. Furthermore AMPK integrates several signaling pathways (including AKT, GSK3, mTORC1, and eEF2) controlling de novo protein synthesis, dysregulation of which is implicated in cognitive syndromes associated with neurodegenerative diseases including AD. Mammalian AMPK is a heterotrimeric protein with a catalytic ? subunit and regulatory ?/? subunit. The ? subunit of AMPK exists in two isoforms: ?1 and ?2, and their roles in AD are unknown. By investigating brain tissue from post mortem human AD patients and a transgenic mouse model of AD, I have found that levels of AMPK?1 are dramatically increased while levels of AMPK?2 are decreased. The central hypothesis of the current project is that disruption of AMPK isoform homeostasis represents a key molecular mechanism of AD pathophysiology. Thus, the objective of this project is to determine whether selective AMPK isoform inhibition (and subsequent altering of AMPK isoform homeostasis) alleviates AD-associated deficits in protein synthesis and memory formation. This project will utilize a novel mouse model in which Prkaa1 and Prkaa2 (genes that encode AMPK ?1 and ?2 subunits, respectively) were removed in excitatory neurons in forebrains and hippocampus late in development, to generate brain- and isoform-specific conditional AMPK?1 and ?2 knockout mice (AMPK?1 cKO and AMPK?2 cKO). We have further crossed the heterozygous AMPK?1/2 cKO mice [AMPK?1(+/-) and AMPK?2(+/-)] with Tg19959 AD mouse model (containing two familial AD mutations: K670N and V717F) to generate Tg19959/AMPK?1(+/-) and Tg19959/AMPK?2(+/-) double mutant mice. Using behavioral, electrophysiological, and biochemical methods, the experiments here will 1) elucidate the effects of genetic repression of AMPK isoforms on AD-associated synaptic plasticity impairments; 2) determine the effects of AMPK isoform suppression in learning and memory deficits in AD model mice; and 3) establish whether specific AMPK isoform reduction improves AD pathology, including brain amyloid deposition and de novo protein synthesis impairments. The experimental findings derived from this project will help elucidate a novel mechanism for AD pathophysiology, shedding a light on potentially new diagnostic biomarkers and therapeutic targets.

Public Health Relevance

Currently, there exists no viable treatment, cure, or preventative intervention for Alzheimer?s disease, a progressive neurodegenerative disease leading to memory loss in the elderly. As the disease progresses, neurons lose their regulation of signaling pathways and energy homeostasis - both of which are critical for maintaining brain health and function. The current project will determine the roles of AMPK isoform homeostasis in aberrant signalling mechanisms underlying Alzheimer?s pathogenesis, potentially revealing new therapeutic targets for treatment and prevention of this devastating disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yang, Austin Jyan-Yu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Zimmermann, Helena R; Yang, Wenzhong; Beckelman, Brenna C et al. (2018) Genetic removal of eIF2? kinase PERK in mice enables hippocampal L-LTP independent of mTORC1 activity. J Neurochem 146:133-144