# AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $358,694

## 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 (Aβ), the
pathological cleavage product of APP, we hypothesize that the reduction of Nedd4-2 induced by Aβ 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 Aβ 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 Aβ 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.

## Key facts

- **NIH application ID:** 10274787
- **Project number:** 3R01NS105615-04S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Nien-Pei Tsai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,694
- **Award type:** 3
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274787

## Citation

> US National Institutes of Health, RePORTER application 10274787, AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability (3R01NS105615-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10274787. Licensed CC0.

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