A substantial amount of clinical reports have confirmed that patients with Alzheimer’s disease are at increased risk for developing seizures and/or epilepsy. This non-psychiatric comorbidity causes significant burden to the patients as well as the caregivers. However, our knowledge in this area is very limited. Understanding the mechanisms underlying Alzheimer’s disease-associated seizures may reveal novel risk factors and provide the opportunity to develop specific anti-epileptic therapies for Alzheimer’s disease patients. Our recent studies discovered that the activity of tumor suppressor p53 is positively correlated with neuronal excitability in vitro and seizure susceptibility in vivo. Because we and others have observed an up-regulation of p53 protein levels induced by amyloid beta (Aβ), we hypothesize that elevated p53 induced by Aβ contributes to elevated neuronal excitability and seizure susceptibility in Alzheimer’s disease. In Aim 1, we propose to determine the cellular mechanism by which p53 promotes neuronal excitability. In Aim 2, we propose to test whether pharmacologically or genetically inhibiting p53 is able to effectively reduce neuronal excitability in the presence of Aβ and seizure susceptibility in an Alzheimer’s disease mouse model. We expect that completion of our project will: (1) elucidate the mechanisms by which p53 promotes excitability; (2) uncover the key molecule (p53) that leads to elevated seizure susceptibility in Alzheimer’s disease; and (3) suggest novel therapeutic targets and potential therapies for Alzheimer’s disease-associated seizures and epilepsy.