AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

University Of Illinois At Urbana-Champaign, Urbana IL

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY/ABSTRACT A substantial amount of clinical reports have confirmed that patients with Alzheimer?s disease are at increased risk for developing seizures and/or epilepsy. The seizures in Alzheimer?s disease have been shown to occur more often with the early-onset disease, particularly when there is a familial presenilin I (PS1) mutation or abnormal expression of amyloid precursor protein (APP). 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. Through support from the parent award, our recent studies have confirmed the role of ubiquitin E3 ligase neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2) in reducing neuronal excitability in vitro and seizure susceptibility in vivo (Zhu et al., PLOS Genet, 2017; Lee et al., Hum Mol Genet, 2018; Zhu et al., J Neurochem, 2019). Based on a preliminary observation showing a reduction of Nedd4-2 in an Alzheimer?s disease mouse model and in primary neuronal cultures treated with amyloid beta (A?), the pathological cleavage product of APP, we hypothesize that the reduction of Nedd4-2 induced by A? contributes to elevated neuronal excitability and seizure susceptibility in Alzheimer?s disease. In the supplemental research Aim 1, we propose to determine the mechanism by which A? induces a reduction of Nedd4-2. In the supplemental research Aim 2, we propose to test whether re-expressing Nedd4-2 is sufficient to reverse neuronal hyperexcitability in the presence of A? in vitro and ex vivo. In the supplemental research Aim 3, we propose to determine whether re-expressing Nedd4-2 is sufficient to reduce seizure susceptibility in an Alzheimer?s disease mouse model in vivo. The supplemental research being proposed is within the scope of the Aim 3 of the parent award in which the function of Nedd4-2 in reducing seizure susceptibility in temporal lobe epilepsy (TLE) is being studied. Through the research on Nedd4-2 in Alzheimer?s disease, we expect our results to: (1) elucidate the mechanism underlying dysregulation of Nedd4-2 in Alzheimer?s disease; (2) uncover an alteration of a key molecule (Nedd4-2) 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.