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.

项目摘要/摘要 大量的临床报告证实，阿尔茨海默氏病的患者处于 增加癫痫发作和/或癫痫病的风险增加。已经显示了阿尔茨海默氏病的癫痫发作 早期发病的频繁发生，尤其是在有家族蛋白I（PS1）突变的情况下发生 或淀粉样前体蛋白（APP）的异常表达。这种非精神病合并症会引起重大 给患者和看护人的负担。但是，我们在这方面的知识非常有限。 了解阿尔茨海默氏病相关的癫痫发作的机制可能揭示出新的风险 因素并提供了为阿尔茨海默氏病患者开发特定的抗癫痫疗法的机会。 通过父母奖的支持，我们最近的研究证实了泛素E3连接酶神经的作用 前体细胞在减少神经元刺激的过程中表达了发达的下调基因4样基因（NEDD4-2） 体内体外和癫痫敏感性（Zhu等，Plos Genet，2017; Lee等，Hum Mol Genet，2018; Zhu 等，J Neurochem，2019）。基于初步观察，显示了NEDD4-2的降低 阿尔茨海默氏病小鼠模型和用淀粉样蛋白β（Aβ）治疗的原发性神经元培养物， APP的病理切割产物，我们假设Aβ诱导的NEDD4-2的还原有助于 在阿尔茨海默氏病中升高神经元的刺激性和癫痫发作的敏感性。在补充研究中 AIM 1，我们建议确定Aβ诱导NEDD4-2降低的机制。在 补充研究目的2，我们建议测试重新表达NEDD4-2是否足以逆转 在体外Aβ存在下神经元过度刺激性。在补充研究目的3中，我们 确定重新表达NEDD4-2是否足以降低癫痫发作的建议 阿尔茨海默氏病小鼠模型在体内。提出的补充研究在于 父母奖的目标3，其中NEDD4-2在降低临时癫痫发作易感性方面的功能 叶癫痫（TLE）正在研究。通过对阿尔茨海默氏病NEDD4-2的研究，我们希望我们 结果：（1）阐明NEDD4-2在阿尔茨海默氏病中的机制； （2）发现 关键分子（NEDD4-2）的改变，导致阿尔茨海默氏病的癫痫发作敏感性升高； （3）建议对阿尔茨海默氏病相关性癫痫发作的新型治疗靶标和潜在疗法 和癫痫。