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

摘要： 阿尔茨海默病（AD）被认为是由多种遗传和环境因素共同作用引起的。 感染因子和感染因子的作用已经争论了几十年。最近的一个多组学，流行病学 一项大型阿尔茨海默病患者队列研究揭示了人类疱疹病毒 6A（HHV6A）与AD。然而，这些研究不能解决哪些HHV 6A特异性基因参与， HHV 6A如何影响中枢神经系统（CNS）细胞，从而加重AD。HHV6A主要是 我们提出了一个问题，即主要的潜伏相关基因 U94A影响与阿尔茨海默病病理学相关的宿主细胞功能。 使用人类细胞系统，我们发现U94A表达损害人类细胞的迁移和成熟。 神经胶质祖细胞（OPC），并导致人类神经元中的突触丢失。初步转录组学和 对U94A感染细胞的蛋白质组学分析表明，参与细胞骨架功能的基因失调， 突触成熟此外，我们发现U94 A的表达增加了Aβ的积累， 在共表达家族性阿尔茨海默病（FAD）相关的突变APPswe的细胞中Tau的磷酸化 变量。这些表型与阿尔茨海默病的早期阶段特别相关， 证据表明，突触和神经突的损失，与弥漫性脱髓鞘，先于认知 损伤基于我们已发表的和初步的数据，我们提出潜伏基因U94A代表 一种使神经细胞易受阿尔茨海默病相关危险因素影响的疾病修饰因子， 并在体外和体内加重阿尔茨海默病的病理。我们提出了三个目标，我们测试 假设（i）U94A表达加剧了来自家族性神经病的iPSC衍生的神经细胞中的Aβ积累， 阿尔茨海默病（FAD）患者，并会加剧神经元和神经胶质细胞损伤，（ii）U94A 在小鼠中FAD突变的情况下的表达将加剧体内细胞病理学，和（iii）在小鼠中FAD突变的情况下的表达将加剧体内细胞病理学， 由U94A引起的细胞损伤足以加重家族性阿尔茨海默氏症的认知缺陷 小鼠模型。这项工作将提供深入了解感染因子在阿尔茨海默氏症中的潜在作用 HHV6A病毒潜伏期不仅是病毒感染的良性状态， 重要的疾病调节因子。

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.