# NAAG Peptidase, Chemobrain, and Alzheimer's disease

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $428,000

## Abstract

Project Summary/Abstract
Cognitive impairments may occur in cancer patients and survivors during or after chemotherapy. Cognitive
deficits associated with neurotoxicity can be subtle or disabling and frequently include disturbances in memory,
attention, executive function and processing speed. Cognitive impairments may go away soon after
chemotherapy is over or may persist for years and yet, there is a paucity of effective treatments. Research has
shown that chemotherapy drugs such as doxorubicin directly disturb synaptic structure by altering its
biochemistry. For example, doxorubicin activate N-methyl D-aspartate (NMDA) receptors leading to
neurotoxicity and accelerated neuronal aging. Critically, some studies demonstrated that dementia occurs
more commonly in cancer patients who had chemotherapy treatment compared to individuals never exposed
to chemotherapy. A search for druggable targets for treating chemobrain led us to hypothesize that inhibiting
an enzyme called NAAG peptidase (NAAGP) may reduce toxicity associated with chemotherapy. NAAGP
catalyzes the hydrolysis of a neuropeptide N-acetylaspartylglutamate (NAAG) to N-acetylaspartate and an
excitatory neurotransmitter glutamate, which may contribute to NMDA-dependent excitotoxicity. In our data, we
show that doxorubicin enhances the deposition of amyloid in Tg2576 mice, a model of Alzheimer’s disease.
We also demonstrate that ZJ43, an inhibitor of NAAGP, mitigates doxorubicin-induced cognitive impairment in
wild-type mice. Therefore, manipulating the NAAG peptidase pathway may be a therapy against cognitive
impairments associated with chemotherapy. Manipulating NAAGP may also prevent accelerated brain aging
and dementia associated with chemotherapy treatment. In this proposal, we will determine whether ZJ43
alleviates cognitive and behavioral phenotypes and improves pathology in Tg2576 and Tau P301S mice
treated with doxorubicin. A successful implementation of the goals of our proposal will bring us closer to
developing a therapy for doxorubicin-associated cognitive disturbances and dementia, and help us to improve
the life quality of cancer patients and survivors.

## Key facts

- **NIH application ID:** 9958819
- **Project number:** 1R21AG067204-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Andrey Tsvetkov
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $428,000
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9958819

## Citation

> US National Institutes of Health, RePORTER application 9958819, NAAG Peptidase, Chemobrain, and Alzheimer's disease (1R21AG067204-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9958819. Licensed CC0.

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