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

慢性癫痫发作对 AD 相关模型中神经精神合并症的影响

基本信息

批准号：
10441520
负责人：
Melissa Leigh Barker-Haliski
金额：
$ 38.88万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441520
关键词：
Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Amyloid beta-Protein Precursor Anxiety Behavioral Caregivers Chronic Clinical Clinical Research Cornea DNA Sequence Alteration Data Deposition Development Disease Disease Progression Early Onset Alzheimer Disease Epilepsy Epileptogenesis Event Exhibits Focal Seizure Functional disorder Genes Genotype Goals Hippocampus (Brain)Immediate-Early Genes Impact Seizures In Vitro Incidence Knockout Mice Knowledge Language Lead Measures Medical Mental Depression Modeling Molecular Mus Mutant Strains Mice Mutation Nature Neuronal Plasticity Pathology Patients Pattern Pre-Clinical Model Process Protein Overexpression Quality of life Reporting Risk Factors Role Seizures Senile Plaques Severities Sleep Wake Cycle Sleep disturbances Synaptic plasticity Testing Transgenic Mice Variant Wild Type Mouse Work abeta accumulation age related aged anxiety-like behavior associated symptom beta amyloid pathology burden of illness circadian comorbidity cytokine experience genetic variant molecular marker neuroinflammation neuropathology neuropsychiatric symptom neuropsychiatry overexpression pre-clinical presenilin presenilin-1 presenilin-2 protein expression risk variant tau Proteins

项目摘要

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.

抽象的：常染色体显性早期发作的阿尔茨海默氏病（ADEOAD）与许多遗传突变，包括淀粉样蛋白前体蛋白（APP）和Presenilin（PSEN）1中的突变。和2个基因。越来越多的证据表明AD患者经常经历未诊断局灶性癫痫发作。实际上，超过30％的AD患者具有最常见的PSEN2基因变体（N141i）报告癫痫发作和应用复制患者的发生率类似报道的癫痫发作，表明过度兴奋性在病理生理学中的作用未开发广告。癫痫和AD都与众多神经精神病合并症有关。有限的临床证据表明，报告癫痫发作的AD患者可能恶化长期疾病轨迹。但是，很少有研究直接解决了慢性在存在AD相关的风险基因的情况下，癫痫发作会影响长期神经精神病学和行为合并症。存在更少的数据，直接定义了年龄依赖的影响关于神经塑性过程的慢性癫痫发作，这也可能是神经精神病学的基础广告合并症。因此，该提议将证明慢性癫痫发作如何依赖于年龄影响神经精神上的合并症和神经塑性相关的蛋白质表达 AD的几种临床前模型，并且不证明淀粉样蛋白β积累（分别为App/PSEN1和PSEN2-N141I）。该建议将确定地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导致AD轨迹恶化的贡献者。目前尚不清楚当癫痫发作发生时。还不清楚这些癫痫发作是否加剧与AD相关的神经精神症状。 ADEOAD风险基因代表未置换的网络过度兴奋性的分子贡献者，这可能会加速疾病的进展在AD的背景下。该项目的主要目标是因此定义与年龄相关的添加剂与ADEOAD相关的危险因素和慢性癫痫发作对发展的影响神经精神病合并症和神经塑性相关蛋白表达的严重程度。