Brain-wide alterations revealed by spatial transcriptomic and proteomic analyses in COVID-19 infection

Abstract Understanding the pathological basis of the neurological symptoms observed following SARS-CoV2 infection is essential to optimizing outcomes and developing therapeutics. To date, small sample sizes and narrow molecular profiling limit the generalizability of findings. We performed proteomics coupled with bulk and spatial transcriptomics in multiple cortical and subcortical regions in postmortem COVID-19 patient brains and matched controls (total n=42). We observed a multi-regional antiviral response and identified broad dysregulation of synaptic and mitochondrial pathways in deep-layer excitatory neurons and up-regulation of neuroinflammatory pathways in glia at the mRNA and protein levels. These changes overlapped those observed in multiple neurodegenerative diseases, including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Our work, based on multiple experimental and analytical methods, shows that severe COVID-19 has a broad impact across cortical and subcortical regions and shares core neuronal and glial changes with neurodegenerative conditions typically associated with aging.