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-NF?B axis by observing receptor ST2 knockout mice or NF?B 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

Public Health Relevance

We discovered a neuroprotective role of brain interleukin33 during aging-related oxidative stress. We aim to explore if interleukin33 deficiency causes aging related neuronal death and senile dementia such as Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZAG1)
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Opanashuk, Lisa A
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University of Texas Health Science Center Houston
Other Basic Sciences
Schools of Dentistry/Oral Hygn
United States
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