COVID, AMYLOID, AND INFLAMMATION
Literature collection of the CovAmInf workgroup.
Editors
Joshua T. Berryman
Abdul Mannan Baig
Artemi Bendandi
Daniel Bonhenry
Mattheos A.G. Koffas
Javier Jarazo, Eveline Santos da Silva, Enrico Glaab, Danielle Perez-Bercoff, Jens C. Schwamborn
The article investigates the impact of SARS-CoV-2 on the midbrain, with a focus on dopaminergic neurons, which are implicated in Parkinson's disease (PD). Researchers used midbrain organoids as an in vitro model for COVID-19 and assessed the direct effects of the virus on dopaminergic neurons and astrocytes over 4- and 28-day post-infection (dpi) culture periods.
The midbrain organoids were exposed to 0.05 moi of SARS-CoV-2 for 16 hours. The study employed an automated image analysis platform to extract features of the cell types present in the midbrain organoids. At 4 dpi, a positive signal for the SARS-CoV-2 nucleocapsid (N) was detected in both the external boundaries and the inner parts of the organoid. Notably, not all TH+ (tyrosine hydroxylase) neurons stained positive for N. The levels of dopaminergic neurons were significantly reduced at both 4 and 28 dpi, with a significant increase in neurite fragmentation observed over time.
The researchers then evaluated SARS-CoV-2 infection in astrocytes by assessing the expression of GFAP and S100b. While their levels and colocalization were reduced during the early stages of infection, they increased over time, although S100b remained significantly lower than control conditions. Dopaminergic neurons were the most affected, with around 40% of TH+ neurons in the midbrain organoid showing positive signal for the virus in short-term cultures.
Differentially expressed genes (DEGs) of midbrain organoids at 4 dpi were enriched using various bioinformatic platforms. Dysregulated pathways associated with DNA damage, cell stress and death, neurodevelopment and neuronal survival, vesicle transport and membrane recycling, COVID-19, and autophagy were identified. Genes related to dopaminergic neuronal migration (ROBO4 and SLIT2) and survival of mature neurons (NOTCH1) were downregulated post-infection.
Furthermore, the study revealed that SARS-CoV-2 infection induced dysregulation of dynein-mediated axonal transport, which is known to lead to neuronal death due to a lack of positive feedback from target-derived neurons towards the neuronal soma. Impairments in this process have been linked to the early stages of PD development. Additionally, mitochondrial metabolism impairments were observed, which can further affect these high energy-demanding neurons.
The findings confirm that SARS-CoV-2 can infect dopaminergic neurons and induce mechanisms leading to neurite fragmentation and neuronal loss, as well as significant changes in the transcriptome. This highlights the need for further research on the interplay between dopaminergic neurons, the blood-brain barrier, and microglia at late infection stages and the potential long-term neurological impairment in COVID-19 patients.
Subjects
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