Impact of the Human Herpesvirus 6A (HHV6A) latency gene U94A on Alzheimer disease pathology

摘要： 阿尔茨海默病(AD)被认为是多种基因和环境因素共同作用的结果 因素，而感染性病原体的作用几十年来一直在争论。最近的一个多组学，流行病学 对大规模阿尔茨海默病患者队列的研究揭示了人类疱疹病毒的特异性和显著相关性 6A(HHV6A)伴AD。然而，这些研究不能确定哪些特定的HHV6A基因参与或 HHV6A可能如何影响中枢神经系统(CNS)细胞以加重AD。由于HHV6A主要是 以潜伏的形式存在于大脑中，我们提出了这样一个问题：主要潜伏期相关基因 U94A影响与阿尔茨海默病病理相关的宿主细胞功能。 利用人类细胞系统，我们发现U94A的表达损害了人类的迁移和成熟 胶质前体细胞(OPC)，并导致人类神经元突触丢失。初步转录和转录 对U94A感染细胞的蛋白质组学分析显示，参与细胞骨架功能的基因异常，并 突触成熟。此外，我们还发现，U94A的表达增加了Aβ和 共表达家族性阿尔茨海默病(FAD)相关突变型APPsWE细胞中Tau的磷酸化 变种。这些表型与阿尔茨海默病的早期阶段特别相关，因为 证据表明，与弥漫性脱髓鞘相关的突触和轴突丢失先于认知 减损。根据我们已发表的初步数据，我们认为潜伏期基因U94A代表 一种疾病修正因素，使神经细胞容易受到阿尔茨海默病相关风险因素的影响， 并在体外和体内加剧阿尔茨海默氏症的病理。我们提出了三个目标，用来测试 假设(I)U94A的表达加剧了β在IPSC来源的神经细胞中的积聚 阿尔茨海默病(FAD)患者，并将加剧神经元和神经胶质细胞损伤，(Ii)U94A 在小鼠FAD突变背景下的表达将加剧体内的细胞病理，以及(Iii) U94A引起的细胞损伤足以加剧家族性阿尔茨海默病的认知障碍 老鼠模型。这项工作将深入了解感染因素在阿尔茨海默氏症中的潜在作用 并将确定HHV6A病毒潜伏期不仅是病毒感染的良性状态，而且是一种 重要的疾病修正因素。

Abstract: Alzheimer’s Disease (AD) is thought to be caused by a combination of multiple genetic and environmental factors, and the role of infectious agents has been debated for decades. A recent multi-omic, epidemiological study of large Alzheimer patient cohorts revealed a specific and significant association of human herpesvirus 6A (HHV6A) with AD. However, these studies could not resolve which HHV6A specific genes were involved or how HHV6A might affect cells of the central nervous system (CNS) to exacerbate AD. As HHV6A is mainly present in the brain in its latent form, we asked the question of whether the major latency associated gene U94A, affects host cells functions that are relevant to Alzheimer disease pathology. Using a human cell system, we found that U94A expression impairs the migration and maturation of human glial progenitor cells (OPCs) and leads to synapse loss in human neurons. Preliminary transcriptomic and proteomic analysis of U94A infected cells showed dysregulation of genes involved in cytoskeletal functions and synaptic maturation. In addition, we found that expression of U94A increases accumulation of Aβ and phosphorylation of Tau in cells co-expressing a familial Alzheimer disease (FAD)-linked, mutant APPswe variant. These phenotypes are particularly relevant for the early stages of Alzheimer disease, as mounting evidence suggests that synapse and neurite loss, associated with diffuse demyelination precede cognitive impairment. Based on our published and preliminary data, we propose that the latency gene U94A represents a disease-modifying factor that renders neural cells vulnerable to Alzheimer disease associated risk factors, and exacerbates Alzheimer’s pathology in vitro and in vivo. We propose three Aims in which we test the hypotheses that (i) U94A expression exacerbates Aβ accumulation in iPSC derived neural cells from familial Alzheimer disease (FAD) patients and will exacerbate neuronal and glial cell impairments, (ii) that U94A expression in the context of FAD mutations in mice will exacerbate cellular pathologies in vivo and (iii) that the cellular impairments caused by U94A are sufficient to exacerbate cognitive deficits in familial Alzheimer’s mouse models. This work will provide insight into the potential role of infectious agents in Alzheimer’s pathology and will establish that HHV6A viral latency is not merely a benign state of viral infection, but an important disease modifying factor.