COVID-19 commonly leads to respiratory issues, yet numerous patients also exhibit a diverse range of neurological conditions, suggesting a detrimental impact of SARS-CoV-2 or the viral Spike protein on the central nervous system. Nonetheless, the molecular pathway behind neurological pathology and the presumed neurotropism of SARS-CoV-2 remains largely unexplored. We generated human cortical organoids (HCOs) derived from human induced pluripotent stem cells (hiPSC) to assess: (1) the expression of SARS-CoV-2 main entry factors
(2) their vulnerability to SARS-CoV-2 infection
and (3) the impact of SARS-CoV-2 infection and exposure to the Spike protein on their transcriptome. Results proved that (1) HCOs express the main SARS-CoV-2 receptors and co-receptors
(2) HCOs may be productively infected by SARS-CoV-2
(3) the viral particles released by SARS-CoV-2-infected HCOs are able to re-infect another cellular line
and (4) the infection resulted in the activation of apoptotic and stress pathways, along with inflammatory processes. Notably, these effects were recapitulated when HCOs were exposed to the Spike protein alone. The data obtained demonstrate that SARS-CoV-2 likely infects HCOs probably through the binding of ACE2, CD147, and NRP1 entry factors. Furthermore, exposure to the Spike protein alone proved sufficient to disrupt their homeostasis and induce neurotoxic effects, potentially contributing to the onset of long-COVID symptoms.