# Protective role of interleukin33 in abnormal neuronal aging and degeneration

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $427,750

## Abstract

Abstract:
 Senile dementia e.g. sporadic late-onset Alzheimer's disease (AD) remains a medical mystery. Recent
studies have linked it to impaired anti-aging response in aged neurons. Our study on interleukin33 (IL33)
supported this hypothesis. IL33 is present in nuclei of over half astrocytes in aged brains. Mice lacking Il33 gene
(Il33-/-) develop neurodegeneration at old age with similarities to late-onset AD (i.e. tau deposition, neuron loss
in the cerebral cortex and hippocampus and impaired cognition/memory). To explore the mechanism, we first
discovered a surge of oxidative damages in the cortical/hippocampal neurons at middle age in mice. Normal
neurons respond by activation of anti-aging mechanisms, e.g. repair of oxidative damages or clearance of
cellular wastes by autophagy and glymphatic drainage. Il33-/- mice failed to do so, but instead went on to develop
AD-like symptom at old age. We hypothesize that IL33 regulates anti-aging response in neurons, and thus, its
deficiency causes chronic neuron death, tau deposition and senile dementia. If it is true, oxidative surge in
neurons at middle age is a time window to identify biomarkers for early diagnosis of AD.
 Our long-term goal is to elucidate the pathogenesis of human senile dementia with this Il33-/- model. As the
first step, we aim to answer two fundamental questions for our hypothesis. Specific Aim 1 is to answer whether
IL33 regulates neuronal anti-aging response though ST2-NFκB axis by observing receptor ST2 knockout mice
or NFκB reporter transgenic mice. Specific Aim 2 is to test if IL33 deficiency causes whole clinic spectrum of
late-onset AD by establishing a novel mouse model. All current mouse models for AD are largely based on
mutant human genes, e.g. amyloid precursor protein (APP). However, these genes are normal in late-onset AD.
Thus, amyloid plaques, a hallmark for AD, largely remains a mystery. We reason that tau deposition in Il33-/-
mice implies a cellular environment for aggregation of abnormal proteins (i.e. APP and tau). Although our Il33-/-
mice do not develop amyloid plaques, it is expected because of structural nature of mouse APP. We will
generating a novel strain by crossing Il33-/- mice to WT hu-APP Tg (an AD- and plaque-free strain), and observe
this new strain develops not only tau deposition and AD-like symptom as Il33-/- mice at old age, but also amyloid
plaque. Success of this model may lead to a breakthrough in understanding amyloidogenesis in senile
dementias. This R21 project fits well with the scope of RFA-20-014

## Key facts

- **NIH application ID:** 9970830
- **Project number:** 1R21AG067311-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** YAHUAN LOU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,750
- **Award type:** 1
- **Project period:** 2020-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970830

## Citation

> US National Institutes of Health, RePORTER application 9970830, Protective role of interleukin33 in abnormal neuronal aging and degeneration (1R21AG067311-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970830. Licensed CC0.

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