The aim of this study was to determine the interaction of peripheral immunity vs. the CNS in the setting of AD pathogenesis at the transcriptomic level in a data driven manner. For this purpose, publicly available gene expression data from the GEO Datasets repository. We performed differential gene expression and functional enrichment analyses were performed on the five retrieved studies: (a) three hippocampal cortex (HC) studies (b) one study of peripheral blood mononuclear cells (PBMC) and (c) one involving neurofibrillary tangle – containing neurons of the entorhinal cortex (NFT EC). Subsequently, BLAST was used to determine protein conservation between human proteins vs. microbial, whereas putative protein / oligopeptide antigenicity were determined via RANKPep. Gene ontology and pathway analyses revealed significantly enriched viral parasitism pathways in both PBMC and NFT – EC datasets, mediated by ribosomal protein families and epigenetic regulators. Among these, a salient viral pathway referred to Influenza A infection. NFT – EC annotations included leukocyte chemotaxis and immune response pathways. All datasets were significantly enriched for infectious pathways, as well as pathways involved in impaired proteostasis and non – phagocytic cell phagosomal cascades. In conclusion, our in silico analysis outlined an ad hoc model of AD pathophysiology in which double hit (PBMC and NFT-EC) viral parasitism is mediated by eukaryotic translational hijacking, and may be further implicated by impaired immune responses. Overall, our results overlap with the antimicrobial protection hypothesis of AD pathogenesis and support the notion of a pathogen – driven etiology.

这项研究的目的是以数据驱动的方式确定转录组水平上AD发病机制中外周免疫与CNS的相互作用。为此，可从GEO数据集存储库中公开获得基因表达数据。我们对五项检索的研究进行了差异基因表达和功能富集分析：（a）三项海马皮质（HC）研究（b）一项关于外周血单核细胞（PBMC）的研究和（c）一项涉及神经原纤维缠结的研究内嗅皮层神经元（NFT EC）。随后，BLAST用于确定人类蛋白质与微生物之间的蛋白质保守性，而推定的蛋白质/寡肽抗原性则通过RANKPep确定。基因本体论和途径分析表明，在核糖体蛋白家族和表观遗传调控因子的介导下，PBMC和NFT – EC数据集中病毒寄生途径明显丰富。其中，重要的病毒途径称为甲型流感感染。NFT – EC注释包括白细胞趋化性和免疫反应途径。所有数据集的感染途径以及蛋白稳态受损和非吞噬细胞吞噬细胞级联反应所涉及的途径均得到了显着丰富。总之，我们的计算机模拟分析概述了AD病理生理学的特殊模型，其中双击（PBMC和NFT-EC）病毒寄生虫是由真核翻译劫持介导的，并且可能与免疫应答受损有关。总体，