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