Impact of Chronic Seizures on Neuropsychiatric Comorbidities in AD-Associated Models

摘要： 常染色体显性早发性阿尔茨海默病（ADEOAD）与许多 基因突变，包括淀粉样前体蛋白（APP）和早老素（PSEN）1 2基因越来越多的证据表明，AD患者经常出现未确诊的症状， 局灶性癫痫事实上，超过30%的AD患者具有最常见的PSEN 2基因变异， （N141 I）报告癫痫发作和APP重复患者具有类似的高发病率， 报告的癫痫发作，这表明过度兴奋在癫痫的病理生理学中的未探索的作用。 AD.癫痫和AD均与许多神经精神共病相关。 有限的临床证据表明，报告癫痫发作的AD患者可能已经恶化， 长期的疾病轨迹。然而，很少有研究直接涉及慢性病如何 存在AD相关风险基因的癫痫发作影响长期神经精神和 行为合并症更少的数据存在直接定义年龄依赖的影响， 慢性癫痫发作对神经可塑性过程的影响，这也可能是神经精神疾病的基础。 AD的合并症因此，这项提案将证明慢性癫痫发作如何与年龄相关 影响神经精神共病和神经可塑性相关蛋白表达 几个AD的临床前模型显示和不显示淀粉样蛋白β积累 (APP/PSEN 1和PSEN 2-N141 I）。该提案将明确解决以下问题： 当慢性癫痫发作影响AD的功能和神经病理学后遗症时， 阐明癫痫发作是否是导致AD轨迹恶化的因素。目前还不清楚 当AD发作时，目前还不清楚这些癫痫发作是否会加剧 与AD相关的神经精神症状。ADEOAD风险基因代表了未充分探索的 网络过度兴奋的分子贡献者，可能加速疾病进展 在AD的背景下。本项目的主要目标是确定年龄依赖性添加剂 ADEOAD相关风险因素和慢性癫痫发作对发育和 神经精神共病的严重程度和神经可塑性相关蛋白表达。

Abstract: Autosomal dominant early-onset Alzheimer's disease (ADEOAD) is associated with numerous genetic mutations, including those in amyloid precursor protein (APP), and presenilin (PSEN) 1 and 2 genes. Growing evidence indicates that patients with AD often experience undiagnosed focal seizures. Indeed, over 30% of AD patients with the most common PSEN2 gene variant (N141I) report seizures and patients with APP duplication have a similarly high incidence of reported seizures, suggesting an unexplored role of hyperexcitability in the pathophysiology of AD. Both epilepsy and AD are associated with numerous neuropsychiatric comorbidities. Limited clinical evidence suggests that AD patients with reported seizures may have worsened long-term disease trajectory. However, few studies have directly addressed how chronic seizures in the presence of AD-associated risk genes affect long-term neuropsychiatric and behavioral comorbidities. Even less data exists to directly define the age-dependent impact of chronic seizures on neuroplasticity processes, which may also underlie neuropsychiatric comorbidities of AD. This proposal will thus demonstrate how chronic seizures age-dependently impact neuropsychiatric comorbidities and neuroplasticity-associated protein expression in several preclinical models of AD that do and do not demonstrate amyloid-beta accumulation (APP/PSEN1 and PSEN2-N141I, respectively). This proposal will definitively address whether and when chronic seizures impact the functional and neuropathological sequelae of AD so as to elucidate whether seizures are a contributor to worsened AD trajectory. It is currently unclear when in the course of AD seizures occur. It is also unclear whether these seizures exacerbate neuropsychiatric symptoms associated with AD. ADEOAD-risk genes represent underexplored molecular contributors to network hyperexcitability, which may accelerate disease progression in the context of AD. The major goal of this project is to thus define the age-dependent additive impact of ADEOAD-associated risk factors and chronic seizures on the development and severity of neuropsychiatric comorbidities and neuroplasticity-associated protein expression.