AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

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 更常发生于早发性疾病，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。

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.