# APOE Regulation of Neuron-Astrocyte Metabolic Coupling in Alzheimer's Disease

> **NIH NIH RF1** · UNIVERSITY OF ARIZONA · 2021 · $1,131,312

## Abstract

PROJECT SUMMARY
 Late onset Alzheimer’s disease (LOAD) is a neurodegenerative disease with a multifactorial etiology and
intersecting genetic and environmental risks, making it a complex systems challenge. Brain functions are
highly energy-dependent, with most of which generated by mitochondria via oxidative phosphorylation. While
the association between LOAD and an early decline in brain glucose metabolism and changes in mitochondrial
function is well-established, therapeutics that universally enhance brain mitochondrial function have yet resulted
in favorable outcomes. As the greatest genetic risk factor for LOAD, the e4 variant of APOE (APOE4) was also
found to affect brain bioenergetics and lipid metabolism via incompletely understood mechanisms. Considering
the metabolically diverse cellular composition of the brain and APOE as an inter-cellular lipid carrier, we propose
that cell type-specific intra-cellular bioenergetic shifts and inter-cellular metabolic uncoupling of fatty acid (FA)
metabolism underlie APOE4-driven AD relevant metabolic phenotypes in the brain. Specifically, we hypothesize
that APOE4-induced disruption to astrocytic clearance of neuronal FAs and subsequent degradation in astrocytic
mitochondria could elicit lipid dysregulation, neuronal dysfunction, neuroinflammation and cognitive decline.
 Program of research proposed herein will determine the mechanisms, at the cellular level, by which APOE
polymorphism alters brain bioenergetics and lipid homeostasis, and eventually LOAD risk. To test our
hypotheses, we will implement three levels of investigations to understand the complex mechanisms underlying
APOE regulation of metabolic coupling between neuron and astrocytes. Aim 1 will determine and differentiate
the effect of APOE isoforms on cellular metabolic shift in neurons and astrocytes using single-cell transcriptomics
and in vitro functional assessment. Using a neuron-astrocyte co-culture system, Aim 2 is designed to investigate
the impact and mechanism by which different isoforms and origins (neuronal- vs. astrocytic) of APOE affect
neuron-astrocyte metabolic coupling, focusing on fatty acid metabolism. Aim 3 will test determine how
perturbations to neuron-astrocyte metabolic coupling mediate APOE4-induced LOAD at-risk phenotypes during
aging in vivo.
 Projected outcomes from this research will elucidate how cell types with distinctive bioenergetic
phenotypes jointly maintain the brain metabolic homeostasis, and how APOE4 increases risk of LOAD by
disrupting the metabolic system of the brain. Translationally, this research will shed light on selective cell
vulnerability in AD development and has the potential to identify APOE genotype-specific and cell type-
specific therapeutic targets to sustain or restore a bioenergetic equilibrium and lipid homeostasis in the brain
that are resilient against synaptic- and cognitive declines in LOAD.

## Key facts

- **NIH application ID:** 10209319
- **Project number:** 1RF1AG068175-01A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Fei Yin
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,131,312
- **Award type:** 1
- **Project period:** 2021-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10209319

## Citation

> US National Institutes of Health, RePORTER application 10209319, APOE Regulation of Neuron-Astrocyte Metabolic Coupling in Alzheimer's Disease (1RF1AG068175-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10209319. Licensed CC0.

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