Abstract
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: Alzheimer’s disease; ApoE; COVID-19; SARS-CoV-2 neurotropism; astrocytes; brain organoids; iPSCs; induced pluripotent stem cells; neuron-astrocyte co-culture; neurons; remdesivir.
【저자키워드】 COVID-19, Remdesivir, Alzheimer's disease, induced pluripotent stem cells, iPSCs, ApoE, SARS-CoV-2 neurotropism, astrocytes, brain organoids, neuron-astrocyte co-culture, neurons, 【초록키워드】 Treatment, SARS-CoV-2, viral infection, SARS-CoV2, Risk factors, severe COVID-19, SARS-COV-2 infection, severity, Infection, COVID-19 severity, Remdesivir, risk factor, SARS-CoV2 infection, Brain, Viral, Culture, pluripotent stem cells, Patient, Alzheimer's disease, APOE4, understanding, organoids, Astrocyte, COVID-19 susceptibility, ApoE, SARS-CoV-2 neurotropism, astrocytes, brain organoids, neurons, Neuron, stem cell, Alzheimer disease, increased risk, help, cultures, direct viral infection, Effect, co-culture, Alter, populations, Cell, genetic risk factor, tested, inhibit, elevated, exhibited, nuclear fragmentation, 【제목키워드】 SARS-CoV-2, response,