Molecular Signatures of Alzheimer's Disease (AD) in SARS‐Cov‐2 Infected Mouse Brains.

Background: COVID‐19 is primarily a respiratory syndrome caused by SARS‐CoV‐2 infection, however, a third of COVID‐19 patients report post‐acute neurological sequelae. A close correlation between COVID‐19 and neurodegenerative diseases poses the question of viral etiology and its effect on pre‐existing disease. In this work, we performed brain transcriptomics to compare gene changes in SARS‐CoV‐infected mice and mouse models of Alzheimer's disease (AD) pathology to investigate the relationship between neuroinflammation, immune response, and associated molecular signature of AD. Method: K18‐hACE2 transgenic mice (6‐8 weeks old) expressing human ACE2 receptor were intranasally infected with SARS‐COV‐2 virus (Ancestral USA/WA1/2020). Mock‐infected mice were used as controls. Animals were euthanized 5‐10 days post‐infection. Brains were harvested, treated for viral deactivation, and processed for mRNA extraction. Brains harvested from an uninfected APP/PS1 mouse model of amyloid pathology (9‐12 mo old) and P301S model of tau pathology (8‐9 mo old) were used for comparison. TopHat was used to align RNA‐Seq using Bowtie mapped to the current reference mouse genome assembly. Cufflinks was used to estimate the abundance of transcripts and test for differential expression and regulation. Result: Assessment of differentially expressed genes (p value <0.05) between SARS‐CoV‐2 infected and uninfected K18‐hACE2 brain samples were compared with RNA from uninfected mouse models of AD. The differentially expressed gene set identified 36 upregulated genes that include disrupted RNA metabolism genes, interferon‐ genes, TNF‐associated genes, ubiquitin‐associated genes, transporters, and enzymes. Downregulation of a single gene Tnfrsf17 that has also been reported in patients with severe Covid‐19 (Table 1) and AD patients was observed. Conclusion: Brain transcriptomic profiling of SARS‐CoV‐2 infected mice revealed gene changes that are consistent with those in AD mouse models of amyloid and tau pathology. Our studies warrant further investigation of viral infections as a causative force of transcriptomic changes that precede neurodegeneration. [ABSTRACT FROM AUTHOR]