AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

项目摘要/摘要 大量的临床报告证实，阿尔茨海默病患者正处于 增加癫痫发作和/或癫痫的风险。阿尔茨海默病的癫痫发作已经被证明 更常发生在早发性疾病中，特别是当有家族性早老素I(PS1)突变时 或淀粉样前体蛋白(APP)表达异常。这种非精神病学的共病引起了显著的 患者和照顾者的负担。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机制可能揭示新的风险 为阿尔茨海默病患者开发具体的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连接酶神经的作用 前体细胞表达发育下调基因4-样(Nedd4-2)降低神经元兴奋性 体外和体内癫痫敏感性(朱等，PLOS Genet，2017；Lee等，Hum Mol Genet，2018；朱 等人，J Neurochem，2019)。基于初步观察显示Ned4-2在 在阿尔茨海默病小鼠模型和用淀粉样β蛋白(Aβ)处理的原代神经元培养中， APP的病理裂解产物，我们假设Aβ诱导的Ned4-2的减少有助于 与阿尔茨海默病患者神经元兴奋性和癫痫敏感性升高有关。在补充研究中 目的1，我们提出了Aβ诱导Ned4-2还原的机制。在 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 A-β存在下的神经元在体外和体外的超兴奋性。在补充研究目标3中，我们 建议确定重新表达Nedd4-2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以下范围 父母奖的目标3，其中Ned4-2在降低癫痫发作易感性方面的作用是暂时的 脑叶癫痫(TLE)正在研究中。通过对Nedd4-2在阿尔茨海默病中的研究，我们希望我们的 结果：(1)阐明Nedd4-2在阿尔茨海默病中调节失调的机制；(2)发现 一个关键分子(Nedd4-2)的改变导致阿尔茨海默病患者癫痫易感性的增加； 以及(3)提出阿尔茨海默病相关癫痫的新治疗靶点和潜在治疗方法 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.