Insights into Neurocognitive Sequelae of COVID‐19 Infection from Studies of Brain Organoids

Abstract

AbstractBackgroundCOVID‐19 has been associated with chronic neurocognitive changes which persist after resolution of the acute infection. Brain organoids composed of different neuronal cell types serve as a useful model to evaluate the underlying effects of SARS‐CoV‐2 infection to the brain and facilitate insights into the neurocognitive sequelae of COVID‐19.MethodA review of studies which used brain organoids to evaluate the effects of COVID‐19 was conducted. The studies were identified from the PubMed/MEDLINE database using the search terms “SARS‐CoV‐2” or “COVID‐19” in combination with “organoid” or “brain” or “3D” or “iPSC”. Articles published in English between 1 Jan 2020 and 31 Mar 2023 were included.ResultWe identified a total of 16 studies which used brain organoids to study SARS‐CoV‐2 neurotropism and downstream effects. Although SARS‐CoV‐2 was able to infect neurons, the extent of neurotropism was limited. Instead, choroidal epithelial cells and glial cells including, astrocytes and microglial, demonstrated significant susceptibility to SARS‐CoV‐2 infection. Furthermore it was observed that certain downstream effects of SARS‐CoV‐2 infection were associated with pathways seen in neurodegenerative diseases like Alzheimer’s Disease (AD). These included findings of reactive astrogliosis, impairment of glutamate and choline transporters, microglial‐mediated synapse loss, increased pTau expression and beta amyloid protein accumulation. Overall, the studies suggested that the neurocognitive manifestations of COVID‐19 may be contributed by neuroinflammatory processes and pathways that are found in chronic neurodegenerative conditions like AD.ConclusionAlthough brain organoid technology remains a relatively new tool, it has provided important insights into the pathophysiology of COVID‐19. The use of “assembloids” to recapitulate interactions between different brain regions and development of high throughput evaluation to analyse transcriptome and epigenome changes of infected brain organoids may be further expanded to allow a better understanding of potential neurodegenerative pathways that may result in neurocognitive changes after a viral infection.