# Aberrant Glycogen Modulates Cerebral Glucose Metabolism in Aging and Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $382,500

## Abstract

Abstract:
The onset of Alzheimer's disease (AD) increases in incidence with age, and an increasing aging demographic
means the number of individuals suffering from AD is expanding rapidly. Changes in cerebral metabolism are
hallmarks of aging therefore it is reasonable to hypothesize that age-associated change in metabolism play
major roles in AD progression. AD brains show clear metabolic impairments, and studies suggest that altered
metabolism drives a cascade of events leading to AD onset. The mechanisms initiating these metabolic
impairments remain a critical knowledge gap in AD research. We recently discovered that aberrant glycogen
aggregates (AD-glycogen) are a universal feature of AD in both human and mice. Increases in AD-glycogen
correlated with higher Braak staging and lower glucose levels in patient specimens. AD-glycogen is both
hyper-phosphorylated and hyper-branched making them architecturally distinct from normal glycogen. We
present strong evidence showing that AD-glycogen modulate brain metabolism through direct binding and
inactivation of the AMP-activated protein kinase (AMPK), a master regulator of central carbon metabolism. We
will first elucidate the molecular events leading to abnormal AD-glycogen formation in vitro and in vivo (Aim 1),
then we will interrogate the impact of AD-glycogen on cerebral metabolism during aging (Aim 2). Finally, we
will assess the efficacy of a novel glycogen-clearing enzyme therapy on brain metabolism, cognition, and AD
neuropathology in vivo (Aim 3). The PI has assembled a multi-disciplinary team of investigators with
complementary skillsets and state-of-art, high resolution, and Omic-based techniques to discover potential
therapeutic options and possibly treat the onset of AD.

## Key facts

- **NIH application ID:** 10142341
- **Project number:** 5R01AG066653-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Ramon C. Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,500
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142341

## Citation

> US National Institutes of Health, RePORTER application 10142341, Aberrant Glycogen Modulates Cerebral Glucose Metabolism in Aging and Alzheimer's Disease (5R01AG066653-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10142341. Licensed CC0.

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