SARS‐CoV‐2 Associated Neurocognitive Disorder (SAND): Molecular validation of a pathogenetic hypothesis

Abstract

AbstractBackgroundType I interferon signalling dysregulation is a hallmark of SARS‐CoV‐2 infection and among significantly perturbed pathways in Alzheimer’s disease. In a previous study, we predicted the involvement of this pathway in the development of SARS‐CoV‐2 Associated Neurocognitive Disorder (SAND) via a crosstalk between peripheral immunity and the CNS. The purpose of this study is to determine whether current data support provide external validation to our pathogenetic hypothesis.MethodData for our validation analyses were leveraged from studies of frontal cortex (FC) transcriptomes donated by Alzheimer’s disease and COVID‐19 patients vs. controls, respectively. An additional dataset of nasal epithelial cells from COVID‐19 patients was also used as a putative crosstalk site. Enrichment analyses were employed to provide an unbiased estimate of the enrichment of Type I interferon responses. Furthermore, we performed a literature search in order to identify studies on the effects of COVID‐19 on two different settings: (a) to determine the effects of peripheral exosome cargo on CNS tissue (b) to determine the cargo of neuronal‐derived exosomes. For enrichment analyses, a false discover rate (FDR) <0.05 was considered statistically significant.ResultThe type I interferon pathway (IFN‐I; GO:0060337) was significantly enriched in both Alzheimer’s disease and COVID‐19 FC transcriptomes, as well as nasal epithelia of COVID‐19 patients. Common genes in both IFN‐I FC signatures included PSMB8, IP6K2, IFI35, EGR1, ISG20, MYD88, IFITM1, SP100, GBP2, IFITM3, OASL, IRF1, IRF2, MX2, IFNA2, IRF9, IFIT3, STAT2, HLA‐C, SAMHD1, IFI27, IFITM2, IRF7, BST2. At least one study reports on miR‐148a and miR‐590 as exosomal cargo of infected non‐neuronal cells capable of affecting IFN‐I responses and inducing microglial activation, supporting the role of exosomes as facilitators of IFN‐I crosstalk between the periphery and the CNS. Correspondingly, at least one study reports on proteopathic seeds as cargo of neuron‐derived exosomes.ConclusionIndependent studies and data support continue to corroborate our hypothesis that type I interferon pathway dysregulation as a result of peripheral – CNS immune crosstalk may mediate neuroinflammation and Alzheimer’s disease‐like pathology as observed in SAND.