AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

AMPA 受体泛素化和病理性突触过度兴奋

基本信息

项目摘要

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.
项目总结/摘要 大量的临床报告已经证实,阿尔茨海默病患者在 发生癫痫和/或癫痫的风险增加。阿尔茨海默氏症的癫痫已经被证明 早发性疾病更常发生,特别是当存在家族性早老素I(PS1)突变时 或淀粉样前体蛋白(APP)的异常表达。这种非精神病性共病导致显著的 给病人和护理人员带来负担。然而,我们在这方面的知识非常有限。 了解阿尔茨海默病相关癫痫发作的潜在机制可能揭示新的风险 这些因素,并提供了机会,开发特定的抗癫痫治疗阿尔茨海默病患者。 通过来自父母奖的支持,我们最近的研究已经证实了泛素E3连接酶神经 前体细胞表达发育下调基因4-like(Nedd 4 -2)降低神经元兴奋性 体外和体内癫痫易感性(Zhu等人,PLOS Genet,2017; Lee等人,分子遗传学,2018;朱 例如,J Neurochem,2019)。根据初步观察,Nedd 4 -2在一个 在阿尔茨海默病小鼠模型和用淀粉样蛋白β(Aβ)处理的原代神经元培养物中, APP的病理性裂解产物,我们假设Aβ诱导的Nedd 4 -2的减少有助于 阿尔茨海默病中神经元兴奋性和癫痫易感性的升高。在补充研究中, 目的1,我们提出确定Aβ诱导Nedd 4 -2减少的机制。在 补充研究目的2,我们建议测试重新表达Nedd 4 -2是否足以逆转 在体外和离体Aβ存在下的神经元过度兴奋性。在补充研究目标3中,我们 我们建议确定重新表达Nedd 4 -2是否足以降低癫痫发作的易感性。 阿尔茨海默病小鼠体内模型。拟议的补充研究属于 父母奖励的目标3,其中Nedd 4 -2在降低癫痫发作易感性中的作用, 叶癫痫(TLE)正在研究中。通过对Nedd 4 -2在阿尔茨海默病中的研究,我们期待我们的 结果:(1)阐明阿尔茨海默病中Nedd 4 -2失调的潜在机制;(2)揭示 导致阿尔茨海默病中癫痫易感性升高的关键分子(Nedd 4 -2)的改变; 以及(3)为阿尔茨海默病相关癫痫发作提供新的治疗靶点和潜在疗法 和癫痫。

项目成果

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Nien-Pei Tsai其他文献

Nien-Pei Tsai的其他文献

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{{ truncateString('Nien-Pei Tsai', 18)}}的其他基金

Transcriptional Mechanism underlying Neuronal Hyperexcitability in FXS
FXS 神经元过度兴奋的转录机制
  • 批准号:
    10746620
  • 财政年份:
    2023
  • 资助金额:
    $ 35.87万
  • 项目类别:
Mechanism of Gp1 mGluR-dependent translation and plasticity
Gp1 mGluR 依赖性翻译和可塑性机制
  • 批准号:
    10516050
  • 财政年份:
    2020
  • 资助金额:
    $ 35.87万
  • 项目类别:
Study of PAK3 in epilepsy-associated defects in synaptic plasticity
PAK3在癫痫相关突触可塑性缺陷中的研究
  • 批准号:
    10046413
  • 财政年份:
    2020
  • 资助金额:
    $ 35.87万
  • 项目类别:
Mechanism of Gp1 mGluR-dependent translation and plasticity
Gp1 mGluR 依赖性翻译和可塑性机制
  • 批准号:
    10094921
  • 财政年份:
    2020
  • 资助金额:
    $ 35.87万
  • 项目类别:
Mechanism of Gp1 mGluR-dependent translation and plasticity
Gp1 mGluR 依赖性翻译和可塑性机制
  • 批准号:
    10469161
  • 财政年份:
    2020
  • 资助金额:
    $ 35.87万
  • 项目类别:
Exploring the role of p53 in synapse development and elimination
探索 p53 在突触发育和消除中的作用
  • 批准号:
    10055071
  • 财政年份:
    2020
  • 资助金额:
    $ 35.87万
  • 项目类别:
Mechanism of Gp1 mGluR-dependent translation and plasticity
Gp1 mGluR 依赖性翻译和可塑性机制
  • 批准号:
    10310451
  • 财政年份:
    2020
  • 资助金额:
    $ 35.87万
  • 项目类别:
AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability
AMPA 受体泛素化和病理性突触过度兴奋
  • 批准号:
    10327201
  • 财政年份:
    2018
  • 资助金额:
    $ 35.87万
  • 项目类别:
AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability
AMPA 受体泛素化和病理性突触过度兴奋
  • 批准号:
    10369620
  • 财政年份:
    2018
  • 资助金额:
    $ 35.87万
  • 项目类别:
AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability
AMPA 受体泛素化和病理性突触过度兴奋
  • 批准号:
    10596721
  • 财政年份:
    2018
  • 资助金额:
    $ 35.87万
  • 项目类别:
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