# Adaptive glycolysis as a regulator of neuronal function and decline

> **NIH NIH K99** · YALE UNIVERSITY · 2024 · $125,809

## Abstract

A foundational, unanswered question of neural metabolism is whether the dramatic reduction in glucose uptake
observed during aging and Alzheimer's disease progression is a cause or consequence of the functional decline
of neurons. Current methods for visualizing the dynamics and effects of metabolism in vivo are too limited to
determine if this plays a role in eventual neuronal dysfunction. Notably, neurons are thought to primarily use
glucose for redox protection via the pentose phosphate pathway (PPP), rather than for production of ATP by
glycolysis, and when glycolysis is upregulated in neurons in vitro it leads to elevated redox damage and
apoptosis. As neuronal stimulation can also temporarily increase glycolytic flux, this suggests there may be an
uncharacterized competitive regulation of glucose use towards balancing either ATP production or redox
protection. Therefore, the goal of this proposal is to develop and utilize genetically-encoded biosensors for key
metabolites in C. elegans neurons to determine the relationship between elevated calcium activity, dynamic
states of glucose metabolism, and redox balance at single cell resolution. Thus, aim 1 of this proposal will utilize
the novel fluorescent sensor HYlight to dynamically measure changes in cellular glycolysis in vivo during
conditions of energy stress, such as with neuronal stimulation. The main goals of this aim are to (1) determine
the relationship between states of high ATP demand and induction of upregulated glycolysis, and (2) elucidate
the molecular mechanisms that enhance glycolysis under these conditions. Aim 2 will determine whether states
of high neuronal glycolysis also lead to increased redox sensitivity in single neurons. Genetically-encoded
biosensors for ROS and NADPH will be used to read out cellular redox state and enable development of an
assay for quantifying degradation in stimulation-induced calcium activity that results from cell-autonomous ROS
accumulation. Finally, the effects of reducing glucose within a single neuron over the lifespan of aging worms
will be compared in the context of calcium activity and behavior to determine whether these effects coincide with
those induced by elevated redox damage. This system described herein would provide a new avenue for
assessing the source and impact of ROS-induced decline and give significant insight into the importance of
balancing glucose metabolism in maintaining neuronal function and behavior during aging. Additionally, it will
provide important career development for the submitting candidate, who will train during the K99 phase under
the mentorship of Dr. Daniel Colón-Ramos at Yale University. This lab has significant expertise in behavioral
neuroscience, which will be critical for advancing the career goals of the candidate in linking single neuron biology
to behavioral changes during aging. This award will also support the candidate’s career goals by providing an
opportunity to learn critical research skill...

## Key facts

- **NIH application ID:** 10890875
- **Project number:** 5K99AG083129-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Aaron Wolfe
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,809
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890875

## Citation

> US National Institutes of Health, RePORTER application 10890875, Adaptive glycolysis as a regulator of neuronal function and decline (5K99AG083129-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890875. Licensed CC0.

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