Wednesday, April 17, 2024
4/17/2024
Project Abstract Epilepsy is a chronic neurological condition characterized by recurrent seizures, affecting 65 million individuals and is recognized as a comorbidity in several neurodegenerative diseases, including Alzheimer’s disease (AD). Identifying targets to prevent the development of epilepsy (i.e., epileptogenesis) is a large unmet need. Antiepileptogenic therapies remain limited, even in preclinical models. Here, we propose to examine a novel target, senescent cells (SCs) in the brain, to determine if ablating these cells can prevent epileptogenesis in the pilocarpine mouse model of temporal lobe epilepsy and in the APdE9 mouse model of AD with comorbid epilepsy. Cellular senescence is a conserved cellular program which halts proliferation and triggers a pro- inflammatory senescence associated secretory phenotype (SASP) in response to damaging stimuli. SCs are of growing interest in neurodegenerative diseases but remain completely unexplored in the context of epilepsy. Epileptogenic insults, such as status epilepticus (SE) robustly trigger DNA damage, a common cause of cellular senescence. Moreover, the pro-inflammatory cytokine profile reported during epileptogenesis shares striking similarities to the SASP. We will use the INK-ATTAC mouse model, which selectively expresses an inducible suicide gene (and GFP) under the control of the p16 promoter; p16 expression is a hallmark of SCs. In Aim 1, we will first determine the cellular identity (glial, neuronal) of p16 positive cells following pilocarpine-induced SE. We will next determine if ablating SCs reduces proinflammatory cytokine expression after SE. Finally, we will determine if ablating SCs reduces the development of spontaneous seizures and/or reduces expression of seizures once they occur. In Aim 2, we will target a model with a different etiology, the APdE9 mouse model of AD, which displays co-morbid seizures, and accumulation of SCs. As in Aim 1, we will first characterize the cellular phenotype of SCs in the APdE9 model. We will next determine if ablation of SCs reduces proinflammatory cytokine levels in APdE9 mice. Finally, we will determine if ablation of SCs reduces spontaneous seizure occurrence in APdE9 mice. By using two models, with very different etiologies and “clinical” presentation (convulsive seizures after pilocarpine, non-convulsive seizures in the APdE9 model), we are positioned to test the overarching hypothesis that SCs contribute to the emergence of spontaneous seizures during epileptogenesis, as compared to an effect that is specific to only a particular model. Cellular senescence is unexamined in epilepsy, thus, these studies have the potential to open new lines of research into the mechanisms of epileptogenesis.
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