# Methylglyoxal drives astrocyte senescence to mediate neurodegeneration in Alzheimer's disease

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2023 · $115,399

## Abstract

PARENT GRANT: PROJECT SUMMARY
Senescent astrocytes and microglia, which accumulate with age and in patients with AD, contribute to
neurodegeneration. A major gap in our knowledge is understanding the mechanisms that lead to astrocyte
senescence. Our long-term goal is to define the molecular targets and therapeutic interventions that slow
aging by inhibiting senescence and to determine their impact on neurodegenerative diseases. The overall
objective in this application is to: 1) define the mechanisms by which the glycolytic by-product methylglyoxal
(MGO) drives astrocyte senescence and 2) enhance the detoxification of MGO to mitigate astrocyte
senescence and neurodegeneration in models of AD. Our central hypothesis is that MGO induces senescence
in astrocytes, which secrete pro-inflammatory senescence-associated secretory phenotype (SASP) factors that
cause the neurodegeneration associated with dementia and AD. The rationale of our hypothesis is based
partly on the fact that astrocytes are known to be the metabolic workhorses of the brain and undertake
glycolysis to provide neurons with lactate. Consequently, astrocytes produce more MGO and show increased
activity of the MGO detoxifying pathways. We observe that MGO, which enhances macromolecular damage,
causes senescence. Thus, strategies to detoxify MGO can provide novel approaches to lowering the risk of AD
and related neurodegeneration in the elderly. We will test the hypothesis by pursuing the following Specific
Aims: 1). Determine the mechanisms by which MGO drives senescence in human iPSC derived astrocytes; 2)
Determine the mechanisms by which senescent astrocytes cause neuronal damage; and 3) Determine the role
of the Trpa1 pathway in modulating MGO-induced senescence and AD pathology in mouse models. We will
use iPSC derived astrocytes to determine the mechanisms by which MGO mediates senescence.
Furthermore, we will use proteomics to define the SASP of MGO-induced senescent astrocytes and determine
the effect of the SASP on iPSC-derived neurons carrying wild type and mutant alleles of tau using co-cultures.
We will genetically and pharmacologically manipulate Trpa1 to detoxify MGO to test its effects on senescence
and associated neurodegeneration in two mouse models of AD. We will combine the treatments to detoxify
MGO and eliminate senescent cells to determine if they are working through the same pathways to inhibit
neurodegeneration. The proposed research is innovative because it will determine a novel function for MGO,
an endogenous metabolite produced during glycolysis, in driving astrocytic senescence and, thus,
neurodegeneration. A key significance of this work will help us understand the link between metabolism,
inflammation, and neurodegeneration. It will also pave the way to developing novel therapies for treating
Alzheimer’s and related dementias based on reducing the presence or activity of senescent cells and by
lowering MGO.

## Key facts

- **NIH application ID:** 10794538
- **Project number:** 3R01AG068288-04S1
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Pankaj Kapahi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $115,399
- **Award type:** 3
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10794538

## Citation

> US National Institutes of Health, RePORTER application 10794538, Methylglyoxal drives astrocyte senescence to mediate neurodegeneration in Alzheimer's disease (3R01AG068288-04S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10794538. Licensed CC0.

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