Cell Stem Cell
Volume 28, Issue 2, 4 February 2021, Pages 331-342.e5
Journal home page for Cell Stem Cell

Short Article
ApoE-Isoform-Dependent SARS-CoV-2 Neurotropism and Cellular Response

https://doi.org/10.1016/j.stem.2020.12.018Get rights and content
Under an Elsevier user license
open archive

Highlights

  • SARS-CoV-2 infects hiPSC-derived neurons, astrocytes, and brain organoids

  • ApoE4 neurons and astrocytes are more susceptible to SARS-CoV-2 infection

  • APOE4 astrocytes exhibit a more severe response to SARS-CoV-2 infection

  • RDV inhibits SARS-CoV-2 infection in neurons and astrocytes

Summary

ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.

Keywords

ApoE
Alzheimer's disease
COVID-19
induced pluripotent stem cells
iPSCs
neurons
astrocytes
neuron-astrocyte co-culture
brain organoids
SARS-CoV-2 neurotropism
remdesivir

Cited by (0)

6

These authors contributed equally

7

These authors contributed equally

8

Lead Contact