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

摘要： 常染色体显性遗传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个基因。越来越多的证据表明，阿尔茨海默病患者经常经历未确诊的情况 局灶性癫痫。事实上，超过30%的AD患者带有最常见的PSEN2基因变异 (N141I)报告癫痫发作和APP重复的患者也有类似的高发病率 报道的癫痫发作，表明高兴奋性在癫痫的病理生理学中的作用尚不清楚 广告。癫痫和阿尔茨海默病都与许多神经精神疾病的并存有关。 有限的临床证据表明，据报道有癫痫发作的AD患者可能已经恶化 长期的疾病轨迹。然而，很少有研究直接解决慢性疾病的程度。 存在AD相关风险基因的癫痫会影响长期的神经精神和 行为并存。直接定义年龄相关影响的数据就更少了 慢性癫痫对神经可塑性过程的影响，这也可能是神经精神病学的基础 AD的合并症。因此，这项提议将证明慢性癫痫发作是如何与年龄相关的 神经精神疾病与神经可塑性相关蛋白表达的影响 几种存在和不存在淀粉样β蛋白蓄积的AD临床前模型 (分别为APP/PSEN1和PSEN2-N141I)。这项提案将明确解决是否 当慢性癫痫发作影响AD的功能和神经病理后遗症时， 阐明癫痫发作是否是AD轨迹恶化的一个因素。目前尚不清楚 当在阿尔茨海默病发作过程中发生。目前也不清楚这些癫痫发作是否会加剧 与阿尔茨海默病相关的神经精神症状。ADEOAD风险基因代表未被开发 网络过度兴奋的分子贡献者，这可能会加速疾病进展 在AD的背景下。这个项目的主要目标是定义与年龄相关的添加剂 ADEOAD相关危险因素和慢性惊厥对发育和癫痫的影响 神经精神合并症的严重性和神经可塑性相关蛋白的表达。

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.