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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：
9895415
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/9895415
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 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 Presenile Alzheimer Dementia 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.

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