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Updated: Aug 26, 2025
Derivation of a Human Brain Organoid with Microglia Development
Published on: January 17, 2025
SARS-CoV-2 promotes microglial synapse elimination in human brain organoids
Samudyata1, Ana O Oliveira1, Susmita Malwade1
1Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Abstract:
Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection initiate neuronal cell death and cause a loss of post-synaptic termini. Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure. We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synapse engulfment. To a large extent, SARS-CoV-2 exposed microglia adopt a transcriptomic profile overlapping with neurodegenerative disorders that display an early synapse loss as well as an increased incident risk after a SARS-CoV-2 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from COVID-19.
Insights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers brain cell death and synapse loss. Microglia contribute to cognitive impairments in COVID-19 patients by eliminating synapses.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Neuropsychiatric issues are frequent in COVID-19 patients.
- Mechanisms behind these neurological effects remain unclear.
Purpose of the Study:
- Investigate SARS-CoV-2 effects on brain cells.
- Elucidate the role of microglia in COVID-19-associated neurological deficits.
Main Methods:
- Utilized a novel brain organoid model with developing microglia.
- Performed single-cell transcriptomic profiling of microglia.
- Analyzed neuronal cell death and synapse loss post-SARS-CoV-2 exposure.
Main Results:
- SARS-CoV-2 infection caused neuronal cell death and loss of postsynaptic termini.
- Microglial engulfment of synapses increased threefold.
- SARS-CoV-2-exposed microglia showed upregulated interferon and migration/engulfment genes.
- Microglial transcriptomic profiles resembled those in neurodegenerative disorders.
Conclusions:
- SARS-CoV-2 disrupts brain circuit integrity through microglia-mediated synapse elimination.
- This pathway may contribute to cognitive impairments observed in COVID-19 recovery.
