# Role of oligodendrocyte-derived IL-33 in brain aging and Alzheimer's disease

> **NIH NIH R56** · TEMPLE UNIV OF THE COMMONWEALTH · 2022 · $533,913

## Abstract

Abstract
The aged brain is thought to be more vulnerable to stresses than its young counterpart, and different in
its coping with neuroinflammation and ability to repair an injury. A better understanding of the brain
aging process will provide valuable information. This knowledge enables one to mitigate age-related
declines in cognitive, emotional, sensory, and motor functions. Such information may also promote
effective strategies for treating age-related neurodegenerative diseases, such as Alzheimer’s disease
(AD). The brain is composed of multiple types of non-neuronal cells besides neurons, and each type
seems to undergo unique age-related changes following its genetic program. Oligodendrocytes (OLs),
a major glial cell population, form myelin sheaths, essential for rapid axonal conduction in the central
nervous system (CNS). OLs also provide metabolic and nutritional support to neurons and contribute to
other homeostatic regulations for axonal communication. Recently, our OL-specific transcriptomic
analyses revealed that IL-33, a member of the IL-1 family known to contribute to neural circuit refining
and neural repair, is increasingly expressed in OLs with age. Consequently, at one year of age, OLs
become the predominant source of IL-33 (> 90% of all IL33-expressing cells) in the mouse CNS.
Interestingly, IL-33 genetic variations are correlated with the risk of AD in patients, and higher levels of
IL-33 in the brain significantly benefited amyloid plaque clearance in mice. Given the critical functions
of IL-33, it is crucial to identify detailed cell-specific mechanisms of IL-33 in the aged brain. To
understand how OL-derived IL-33 shapes brain aging and AD-like disease progression, we will employ
mouse genetic tools that allow OL-specific or all CNS macroglia (OL lineage glia and astrocytes)-
targeted IL-33 conditional knockout (cKO). More specifically, in Aim1, we will determine whether the
loss of IL-33 expression selectively in OLs or all macroglia affects oligodendroglial integrity and
regenerative features. We will also utilize single-cell transcriptomic analyses with those mice to
determine how OL-derived IL-33 affects their properties and those of their neighbor cells. In Aim2, by
applying the same genetic manipulations to a mouse model of AD (APP/PS1), we will determine
whether OL-specific IL-33 regulates AD-like diseases and cognitive deficits, as well as microglia-
mediated clearance of beta-amyloid (Ab) deposits. Finally, in Aim3, we will also overexpress IL33 in
OLs or all macroglia to see if higher levels of IL33 impact OL integrity and Ab clearance. If successfully
conducted, this study will advance our understanding of cell-cell interactions, especially those
mediated by IL-33 in brain aging and during the progression of AD. Our results may promote the
development of a therapeutic strategy with an oligodendroglia-targeted approach and identify related
molecular mechanisms and targets for treating AD patients.

## Key facts

- **NIH application ID:** 10670496
- **Project number:** 1R56AG078565-01
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Shin H Kang
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $533,913
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670496

## Citation

> US National Institutes of Health, RePORTER application 10670496, Role of oligodendrocyte-derived IL-33 in brain aging and Alzheimer's disease (1R56AG078565-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10670496. Licensed CC0.

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