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: 10274787
• 负责人: Nien-Pei Tsai
• 金额: $ 35.87万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10274787
• 关键词: AMPA Receptors; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Antiepileptic Agents; Area; Award; Caregivers; Clinical; Development; Epilepsy; Genes; Genets; In Vitro; Knowledge; Mutation; Neurons; Onset of illness; Parents; Pathologic; Patients; Predisposition; Proteins; Reporting; Research; Risk; Risk Factors; Role; Seizures; Synapses; Temporal Lobe Epilepsy; Testing; Ubiquitination; base; comorbidity; early onset; in vivo; in vivo Model; mouse model; nerve stem cell; neuronal excitability; new therapeutic target; novel; parent grant; presenilin; therapeutic target; ubiquitin-protein ligase

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.

项目概要/摘要 大量临床报告证实，阿尔茨海默病患者处于 阿尔茨海默氏病的癫痫发作风险增加。 在早发性疾病中更常见，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，这种非精神疾病会导致严重的并发症。 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机制可能会揭示新的风险 因素并为开发针对阿尔茨海默病患者的特定抗癫痫疗法提供了机会。 通过家长奖的支持，我们最近的研究证实了泛素E3连接酶神经元的作用 前体细胞表达发育下调基因4样（Nedd4-2）以降低神经兴奋性 体外和体内癫痫易感性（Zhu et al., PLOS Genet, 2017；Lee et al., Hum Mol Genet, 2018；Zhu 等人，J Neurochem，2019）基于初步观察显示 Nedd4-2 减少。 阿尔茨海默病小鼠模型和用β淀粉样蛋白（Aβ）处理的原代神经元培养物中， APP 的病理裂解产物，我们发现 Aβ 诱导的 Nedd4-2 的减少有助于 在补充研究中，阿尔茨海默病的神经元兴奋性和癫痫易感性升高。 目标 1，我们建议确定 Aβ 诱导 Nedd4-2 减少的机制。 补充研究目标 2，我们建议测试重新表达 Nedd4-2 是否足以逆转 在补充研究目标 3 中，Aβ 存在时的体外和离体神经元过度兴奋。 提议确定重新表达 Nedd4-2 是否足以降低癫痫发作的易感性 所提出的补充研究属于阿尔茨海默病小鼠模型的范围。 家长奖的目标 3，其中 Nedd4-2 在降低颞叶癫痫发作易感性方面的功能 通过对 Nedd4-2 在阿尔茨海默病中的研究，我们预计我们的研究结果将有助于发现叶性癫痫 (TLE)。 结果：(1) 阐明阿尔茨海默病中 Nedd4-2 失调的机制；(2) 揭示 关键分子（Nedd4-2）的改变导致阿尔茨海默氏病癫痫发作易感性升高； (3) 为阿尔茨海默病相关癫痫发作提出新的治疗靶点和潜在疗法 和癫痫。