# Isoform-specific roles of AMPK in synaptic failure and memory deficit in Alzheimer's Disease

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2020 · $526,340

## Abstract

Project Summary/Abstract
The basic molecular mechanisms associated with Alzheimer’s disease (AD) remain a critical knowledge gap
that prevents identification of effective therapeutic targets and diagnostic/prognostic biomarkers. The current
proposal will address this gap by studying the role of signaling pathways associated with AMP-activated
protein kinase (AMPK) isoforms in AD. AMPK functions as a central cellular energy sensor to maintain energy
homeostasis. Moreover, AMPK is a nexus to incorporate multiple signaling pathways for de novo protein
synthesis (mRNA translation). Importantly, both disruptions in energy homeostasis and impairments in de novo
protein synthesis are implicated in cognitive syndromes associated with neurodegenerative diseases, including
AD. The kinase catalytic subunit of AMPK exists in two isoforms in brain: α1 and α2, and their roles in synaptic
plasticity and memory are unknown. We generated brain- and isoform-specific conditional AMPKα1 and α2
knockout mice (AMPKα1 cKO and AMPKα2 cKO), and performed behavioral, electrophysiology, imaging, and
biochemical tests to characterize isoform-specific phenotypes. Driven by our preliminary data, our central
hypothesis is that disruption of AMPK isoform homeostasis represents a key molecular mechanism underlying
AD-associated impairments of synaptic plasticity and memory defects. Three specific aims are formulated to
test the hypothesis. Aim 1 seeks to identify isoform-specific roles of AMPK in hippocampal synaptic plasticity
and memory formation. Aim 2 is designed to determine AMPK isoform-specific regulation of synaptic failure
and memory impairment in Tg19959 AD mouse model. Aim 3 is designed to elucidate AMPK isoform-specific
effects on de novo protein synthesis and brain Aβ pathology in Tg19959 AD mouse model. The project
proposes in-depth analyses using multiple state-of-art methods in neuroscience and AD, including mouse
genetics, synaptic electrophysiology, confocal imaging, and behavioral tests. Moreover, novel methods to
measure de novo protein synthesis combined with mass spectrometry/proteomics approach will be applied to
reveal identities of proteins in AD brains whose synthesis is dysregulated because of abnormal signaling due
to disruption of AMPK isoform homeostasis. This multidisciplinary approach will enable us to identify detailed
cellular/molecular mechanisms associated with aberrant AMPK signaling in AD pathogenesis, providing
insights into novel therapeutic targets and diagnostic biomarkers for AD and other dementia syndromes.

## Key facts

- **NIH application ID:** 9925166
- **Project number:** 5R01AG055581-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Tao Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $526,340
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925166

## Citation

> US National Institutes of Health, RePORTER application 9925166, Isoform-specific roles of AMPK in synaptic failure and memory deficit in Alzheimer's Disease (5R01AG055581-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9925166. Licensed CC0.

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