# Metabolic Mechanisms in Locus Coeruleus Neuron Vulnerability in Neurodegenerative Disease

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $788,562

## Abstract

PROJECT SUMMARY
 Locus coeruleus (LC) dysfunction and degeneration occurs early in Alzheimer’s Disease (AD). LC
degeneration also occurs early in other AD-related neurogenerative disorders, including Down Syndrome (DS)
and Parkinson’s Disease (PD). Substantial evidence links LC degeneration in these conditions with clinically
meaningful measures of disease progression. While studies support mitochondrial and metabolic mechanisms
causing LC vulnerability in AD and related neurodegenerative disease, the mechanisms are poorly understood.
My laboratory has new, unique data demonstrating early and selective LC degeneration in a mouse mutant for
the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2). While several mouse models for AD,
DS and PD show LC dysfunction and degeneration, strikingly, the Gpt2-null mouse shows the earliest LC
degeneration (by postnatal day 18) of any mouse mutant thus far described. Importantly, recent data also
support a link between GPT2-mediated metabolism and AD. Therefore, the study of GPT2-mediated
mechanisms in LC health and degeneration provides an important opportunity to understand mechanisms of
early LC vulnerability with broad significance to AD and related neurodegenerative disorders. The overriding
objective of this R01 application is to define early metabolic mechanisms of LC vulnerability in Gpt2-null mice,
and also in AD and DS mouse models, across the lifespan, including in gene-by-environment (GXE)
experiments using an extended wakefulness paradigm. Our central hypothesis is that the vulnerable LC –
across neurodegeneration mouse models – will exhibit signatures of defective metabolic mechanisms that will
be apparent early, prior to LC neuronal death. In Aim 1, we will define the transcriptomic and metabolomic
signatures of vulnerable LC neurons in the Gpt2-null mouse and in AD and DS mouse models, preceding and
during neuronal death. In Aim 2, we will determine the cell-type specific requirements for Gpt2 in LC through
conditional mutagenesis of Gpt2 in LC noradrenergic neurons or in glia. Finally, in Aim 3, we will define the
extent to which Gpt2 mutation (in the Gpt2 heterozygote, Gpt2+/-) enhances LC vulnerability in adult brain,
using provocations such as an extended wakefulness paradigm, or mating the Gpt2+/- mutation to AD mouse
models. Sleep is an important brain function regulated by LC that has been implicated in disease progression
in AD. In our preliminary data, we observe accelerated LC degeneration in adult Gpt2+/- mutant brain after
provocation using an extended-wakefulness paradigm. Overall, the research in this R01 application will have a
sustained impact because our finding of early LC neurodegeneration in the Gpt2-null mouse represents an
important opportunity to advance our understanding of the early metabolic mechanisms of vulnerability in LC
neurons. Because metabolite supplements that augment these GPT2-mediated mechanisms are available, this
research may lead to important n...

## Key facts

- **NIH application ID:** 10892599
- **Project number:** 1R01AG087455-01
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Eric M Morrow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $788,562
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892599

## Citation

> US National Institutes of Health, RePORTER application 10892599, Metabolic Mechanisms in Locus Coeruleus Neuron Vulnerability in Neurodegenerative Disease (1R01AG087455-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10892599. Licensed CC0.

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