Modulation of Alzheimers disease by Herpes simplex virus infection

阿尔茨海默病S病(AD)影响着数以百万计的美国人，并导致显著的发病率和死亡率。尽管阿尔茨海默病的遗传决定因素在过去30年中一直是研究的主要焦点，但对导致AD病理和进展的辅助因素的认识有限。最近的遗传关联表明先天免疫改变对AD的风险，表明环境因素，如感染，可能调节大脑免疫功能，也可能在AD中发挥作用。先前的研究表明，嗜神经性疱疹病毒的慢性感染可能是AD病理发展的一个因素。特别是，在AD大脑和β淀粉样斑块中发现了单纯疱疹病毒1型(HSV-1)DNA。通过对大RNA序列进行仔细的多尺度网络分析。在加速药物伙伴关系-AD(AMP-AD)联盟内的数据集中，我们观察到AD患者多个大脑区域中来自几个疱疹病毒家族成员的转录本增加，我们发现HSV-1的表达与AD患者的临床痴呆评分有关。值得注意的是，这一观察结果在三个独立的AMP- Ad RNA-seq研究。通过观察我们的病毒/AD相关基因，我们发现了病毒模仿的证据 转录调控网络的镜头。我们已经确定了与病毒表达相关的候选转录因子及其下游靶点，以及调节这些转录因子活性的激酶。此外，HSV-1转录本与APP加工的几个关键调节因子的表达增加有关。我们建议通过一系列实验来探索这种挑衅性的转录数据，这些实验将确定疱疹病毒编码蛋白的表达和HSV-1感染是否有助于AD的发生和发展。我们假设嗜神经性疱疹病毒感染改变了已知AD基因的转录调控网络，从而驱动病理。将进行两条平行的调查路线。第一个将结合多学科团队的经验，结合神经病理学、HSV-1生物学、小鼠HSV感染和RNA-SEQ分析，直接询问(1)HSV-1活跃病毒感染是否可以改变AD病理或增强AD病理模型小鼠的原有病理，(2)对感染HSV-1的AD小鼠AD相关RNA表达的变化进行纵向评估。通过我们的比较方法和计算模型，我们将描述 HSV-1感染对已知的AD通路和神经病理特征产生影响。第二个将利用腺相关病毒载体来表达AMP-AD RNA-seq中确定的候选转录因子。研究领域：脑片培养和AD病理的小鼠模型。因此，我们将建立新的模型和测试程序，包括体外和体内模型，使我们能够探索我们的挑衅性RNA序列。AMP-AD数据可以迅速为AD的新的抗病毒治疗方法提供信息。

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.