Integrated understanding of complex viral network biology in Alzheimer's Disease

长期以来，研究人员一直怀疑致病微生物可能导致 阿尔茨海默病（AD），但微生物相关抗原是否代表因果成分的问题 或者是神经退行性变的机会性乘客是难以解决的。在此，我们建议 扩展我们的初步工作映射生物网络的基础上两个不同的AD相关 使用从人类受试者收集的独立死后数据集进行表型分析。首先，我们应用一个 从测量的“临床前AD”样本建立区域特异性生物网络的计算方法 来自符合AD的神经病理学标准，但在治疗时认知完整的个体。 死亡具体来说，我们从激光捕获显微切割的神经元中构建调控网络， 内嗅皮层（EC）和海马（HIP）组织，并比较临床前AD和对照组的结构 网络.我们使用网络分析来识别临床前干扰的几个子网络和关键驱动因素。 AD.网络的功能基因组学分析鉴定了许多与病毒易感性位点相关的富集 在网络驱动因素中，包括C2 H2锌指，G4-四链体活性和miR-155在 调节多种促病毒因子和抗病毒因子。第二个独立数据集的初步网络分析 表征具有“临床AD”的个体确定了病毒网络机制的更直接证据。 活动AD。下一代DNA和RNA测序的可用性使我们能够评估直接 病毒序列的存在，并量化与AD的关联。我们建立了主机的初步网络模型- 病毒调节相互作用和病毒-病毒相互作用，以将病毒种类与认知障碍的严重程度相关联， 损伤和神经病理学。我们发现的证据表明，病毒宿主景观是由两个竞争 以及多种病毒之间的协同作用，对淀粉样前体蛋白产生集体影响 (APP)加工、细胞骨架组织、蛋白质合成和先天免疫应答。我们确认了 与病毒丰度相关的DNA变异（vQTL），并发现vQTL与AD增加相关 风险，临床痴呆严重程度和神经病理学严重程度，表明共同的遗传基础， AD、AD神经病理学的严重程度和特定病毒种类的丰度。我们建议执行 计算和实验工作，以进一步阐明具体的网络机制因果驱动程序或 AD病理生理学中的病毒病原体。具体来说，我们的目标是i）绘制和模拟特定病毒的作用， 在临床前和临床AD中调节致病性分子、遗传和临床网络，ii） 评估C2 H2锌指蛋白和G-四链体序列在介导分子病理学中的作用 和iii）鉴定和评估介导病毒对AD的作用的特异性分子， 临床前和临床AD的分子病理学。

Investigators have long suspected that pathogenic microbes might contribute to the onset or progression of Alzheimer's disease (AD), but the question of whether microbe-related antigens represent a causal component of AD, or are an opportunistic passenger of neurodegeneration is difficult to resolve. Here we propose to expand on our preliminary work mapping biological networks underlying two distinct AD-associated phenotypes using independent post-mortem data sets collected from human subjects. First, we apply a computational approach to build region-specific biological networks from `preclinical AD' samples measured from individuals that meet neuropathological criteria for AD, but who were cognitively intact at the time of death. Specifically, we construct regulatory networks from laser capture microdissected neurons collected from entorhinal cortex (EC) and hippocampal (HIP) tissue and compared the structure of preclinical AD and control networks. We use network analysis to identify several sub-networks and key drivers perturbed in preclinical AD. Functional genomic analysis of networks identified many enrichments relevant to viral susceptibility loci among network drivers, including roles for C2H2 zinc fingers, G4-quadruplex activity, and miR-155 in regulating diverse pro and anti-viral factors. Preliminary network analysis of a second independent data set characterizing individuals with `clinical AD' identified more direct evidence for network mechanisms of viral activity in AD. The availability of next-generation DNA and RNA sequencing allowed us to evaluate the direct presence of viral sequences, and quantify association with AD. We built preliminary network models of host- virus regulatory interactions and virus-virus interactions to correlate viral species with the severity of cognitive impairment and neuropathology. We find evidence that the virus-host landscape is shaped by both competitive and synergistic interactions between multiple viral species, with collective impacts on amyloid precursor protein (APP) processing, cytoskeletal organization, protein synthesis and innate immune response. We identified host DNA variants that associate with viral abundance (vQTL), and found that vQTLs associate with increased AD risk, clinical dementia severity, and neuropathology severity, indicating a shared genetic basis linking risk for AD, severity of AD neuropathology, and abundance of specific viral species. We propose to perform computational and experimental work to further elucidate the specific network mechanisms causal drivers or viral pathogens in AD pathophysiology. Specifically, we aim i) to map and models the roles of specific viral species in modulating pathogenic molecular, genetic, and clinical networks in preclinical and clinical AD, ii) to evaluate the roles of C2H2 zinc finger proteins and G-quadruplex sequences in mediating molecular pathology of preclinical and clinical AD, and iii) to identify and evaluate specific molecules that mediate viral effects upon the molecular pathology of preclinical and clinical AD.