# Development of new tools to explore the role of oligodendrocyte-derived carnosine in Alzheimer Disease

> **NIH NIH R03** · NORTHWESTERN UNIVERSITY · 2024 · $320,000

## Abstract

The lipid peroxidation byproduct acrolein (systematic name: propenal), is a highly toxic aldehyde that exerts
strong toxic effects by covalently binding to surrounding macromolecules, such as proteins, RNA, DNA, and
lipids. Due to the toxicity, cellular mechanisms evolved to detoxify acrolein by quenching acrolein and turning it
into a non-toxic compound. In the CNS, acrolein is quenched by carnosine. Carnosine is generated by the
enzyme Carnosine synthase 1 (Carns1). Aging is associate with reduced levels of carnosine in the brain.
Restoring carnosine levels through food supplementation with carnosine restores the age-related reduction in
brain activity in both mouse models and human patients. Elevated levels of the toxicant acrolein were found in
the brains of Alzheimer disease (AD) patients at the preclinical stage, suggesting that lack of acrolein de-
toxification by carnosine contributes to the pathogenesis at early stages of the disease. Nevertheless, the role
carnosine-mediated detoxification in AD disease etiology is unknown, partially due to lack of appropriate
experimental models. In this proposal we will develop genetic mouse models that will enable us to reduce the
levels of carnosine specifically in the CNS, to explore the role of carnosine in aging and in AD etiology.
In our preliminary studies, we found that the enzyme Carns1 is expressed in the CNS solely by mature
oligodendrocytes. Although carnosine is a ubiquitous metabolite in the body, we found that oligodendrocyte-
specific ablation of Carns1 dramatically reduces the level of carnosine in the CNS, suggesting that
oligodendrocytes are the sole source of carnosine in the CNS. We also found that oligodendrocyte-derived
carnosine protects the CNS from inflammation and reduces the spread of damaged areas marked by acrolein
adducts. In this proposal we hypothesize that oligodendrocyte-derived carnosine play a fundamental role in
acrolein accumulation in the CNS of aged and AD patients.
We will develop new genetic tools to explore the link between oligodendrocytes-derived carnosine, aging, and
AD. In the first aim we will develop Carns1 conditional allele that will enable us to reduce carnosine levels
specifically in the CNS. In the second aim we will explore the role of oligodendrocyte-derived carnosine in disease
progression in two mouse models of amyloid pathology.

## Key facts

- **NIH application ID:** 10887022
- **Project number:** 1R03AG087284-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Benayahu Elbaz-Eilon
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $320,000
- **Award type:** 1
- **Project period:** 2024-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887022

## Citation

> US National Institutes of Health, RePORTER application 10887022, Development of new tools to explore the role of oligodendrocyte-derived carnosine in Alzheimer Disease (1R03AG087284-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10887022. Licensed CC0.

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