Modulation of Alzheimers disease by Herpes simplex virus infection

单纯疱疹病毒感染对阿尔茨海默病的调节

• 批准号: 10615903
• 负责人: Martin C Darvas
• 金额: $ 43.02万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10615903
• 关键词: APBA2 gene; APPBP2 gene; ATRX gene; Acceleration; Affect; Age; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Amyloid; Area; Behavioral; Biology; Brain; Brain region; Clinical; Cognition; Computer Models; DNA; Data; Data Set; Dementia; Development; Elderly; Environmental Risk Factor; Etiology; Event; Family member; Female; Gender; Gene Expression; Gene Expression Regulation; Genes; Genetic Determinism; Genetic Transcription; Genotype; Glycoproteins; Herpes Simplex Infections; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Human; Human Herpesvirus 6; Infection; Investigation; Link; Medicine; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Neurodegenerative Disorders; Pathologic; Pathology; Pathway Analysis; Patients; Phosphotransferases; Procedures; Proteins; Research; Senile Plaques; Simplexvirus; Slice; Testing; Therapeutic; Time; Transcript; Viral; Viral Physiology; Virus Diseases; adeno-associated viral vector; amyloid pathology; amyloid precursor protein processing; antimicrobial peptide; apolipoprotein E-4; behavior change; beta-site APP cleaving enzyme 1; candidate identification; chronic infection; cofactor; comparative; differential expression; endophenotype; experience; experimental study; genetic association; immune function; in vivo; in vivo Model; insight; intraperitoneal; lens; male; mimicry; mortality; mouse model; multidisciplinary; network models; neuropathology; neurotropic; novel; presenilin-1; tau Proteins; transcription factor; transcription regulatory network; transcriptome sequencing; transcriptomics

Alzheimer 's disease (AD) affects millions of Americans and causes significant morbidity and mortality. Although genetic determinants of AD have been a major focus of research over the last three decades, there is limited insight into co-factors that contribute to AD pathology and progression. Recent genetic associations implicating alterations in innate immunity to risk for AD, suggest that environmental factors, such as infection, may modulate brain immune function and could also play a role in AD. Previous studies have suggested that chronic infection of neurotropic herpesviruses could be one factor that contributes to the development of AD pathology. In particular, herpes simplex virus type 1 (HSV-1) DNA has been found in AD brains and in β-amyloid plaques. Through careful multiscale network analysis of the large RNA-seq. datasets within the Accelerating Medicines Partnership-AD (AMP-AD) consortium, we have observed an increased abundance of transcripts derived from several herpesvirus family members across multiple brain regions from subjects with AD, and we have found that HSV-1 expression was associated with the clinical dementia score of AD patients. Notably, this observation has been replicated across three independent AMP- AD RNA-seq studies. We found evidence of viral mimicry upon viewing our viral/AD-associated genes through the lens of transcriptional regulatory networks. We have identified candidate transcription factors and their downstream targets associated with viral expression, as well as kinases that regulate activity of those transcription factors. Additionally, HSV-1 transcripts were associated with increased expression of several key regulators of APP processing. We propose to explore this provocative transcriptomic data using a set of experiments that will determine if expression of herpesviruses encoded proteins and HSV-1 infection contributes to the development and progression of AD. We hypothesize that neurotropic herpesvirus infection alters transcriptional regulatory networks of known AD genes to drive pathology. Two parallel lines of investigation will be conducted. The first will combine the experience of the multidisciplinary team with neuropathology, HSV-1 biology, HSV infection in mice and RNA-seq analysis to directly ask (1) whether active viral infection with HSV-1 can alter AD pathology or enhance preexisting pathology in mouse models of AD pathology, and (2) perform longitudinal assessments of changes in AD-relevant RNA expression in HSV-1 infected AD mice. Through our comparative approach and computational modeling, we will characterize how HSV-1 infection impacts known AD pathways and neuropathological features. The second will leverage the use of adeno-associated viral vectors to express candidate transcription factors identified in AMP-AD RNA-seq. studies in: brain slice cultures and mouse models of AD pathology. As a result, we will establish new models and a testing procedure including ex vivo and in vivo models that allow us to explore our provocative RNA-seq. AMP-AD data in way that could rapidly inform a novel anti-viral based therapeutic approach to AD.

阿尔茨海默病（AD）影响了数百万美国人，并导致了显著的发病率和死亡率。尽管在过去三十年中，阿尔茨海默病的遗传决定因素一直是研究的主要焦点，但对阿尔茨海默病病理和进展的辅助因素的了解有限。最近的遗传关联暗示先天免疫对阿尔茨海默病风险的改变，表明环境因素，如感染，可能调节大脑免疫功能，也可能在阿尔茨海默病中发挥作用。先前的研究表明，嗜神经疱疹病毒的慢性感染可能是导致AD病理发展的一个因素。特别是，在阿尔茨海默病的大脑和β-淀粉样斑块中发现了1型单纯疱疹病毒（HSV-1） DNA。通过仔细的多尺度网络分析大RNA-seq。在加速药物合作伙伴关系-AD （AMP-AD）联盟的数据集中，我们观察到来自AD患者多个大脑区域的几种疱疹病毒家族成员的转录物丰度增加，并且我们发现HSV-1表达与AD患者的临床痴呆评分相关。值得注意的是，这一观察结果在三个独立的AMP-中得到了重复