SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19

Zhouyi Rong; Hongcheng Mai; Saketh Kapoor; Victor G. Puelles; Jan Czogalla; Julia Schädler; Jessica Vering; Claire Delbridge; Hanno Steinke; Hannah Frenzel; Katja Schmidt; Özüm Şehnaz Çalışkan; Jochen Martin Wettengel; Fatma Cherif; Mayar Ali; Zeynep Ilgin Kolabas; Selin Ulukaya; Izabela Horvath; Shan Zhao; Natalie Krahmer; Sabina Tahirović; Ali Önder Yildirim; Tobias Bruno Huber; Benjamin Ondruschka; Ingo Bechmann; Gregor Ebert; Ulrike Protzer; Harsharan S. Bhatia; Farida Hellal; Ali Ertürk

doi:10.1101/2023.04.04.535604

NeurosciencebioRxivApr 4, 2023

Preprint

SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19

Zhouyi Rong iD, Hongcheng Mai iD, Saketh Kapoor, Victor G. Puelles iD, Jan Czogalla iD, Julia Schädler iD, Jessica Vering, Claire Delbridge iD, Hanno Steinke iD, Hannah Frenzel, Katja Schmidt iD, Özüm Şehnaz Çalışkan iD, Jochen Martin Wettengel iD, Fatma Cherif iD, Mayar Ali iD, Zeynep Ilgin Kolabas iD, Selin Ulukaya iD, Izabela Horvath iD, Shan Zhao iD, Natalie Krahmer iD, Sabina Tahirović iD, Ali Önder Yildirim iD, Tobias Bruno Huber iD, Benjamin Ondruschka iD, Ingo Bechmann iD, , Ali Ertürk iD

Abstract

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been associated mainly with a range of neurological symptoms, including brain fog and brain tissue loss, raising concerns about the viruss acute and potential chronic impact on the central nervous system. In this study, we utilized mouse models and human post-mortem tissues to investigate the presence and distribution of the SARS-CoV-2 spike protein in the skull-meninges-brain axis. Our results revealed the accumulation of the spike protein in the skull marrow, brain meninges, and brain parenchyma. The injection of the spike protein alone caused cell death in the brain, highlighting a direct effect on brain tissue. Furthermore, we observed the presence of spike protein in the skull of deceased long after their COVID-19 infection, suggesting that the spikes persistence may contribute to long-term neurological symptoms. The spike protein was associated with neutrophil-related pathways and dysregulation of the proteins involved in the PI3K-AKT as well as complement and coagulation pathway. Overall, our findings suggest that SARS-CoV-2 spike protein trafficking from CNS borders into the brain parenchyma and identified differentially regulated pathways may present insights into mechanisms underlying immediate and long-term consequences of SARS-CoV-2 and present diagnostic and therapeutic opportunities. Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/535604v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@b223eforg.highwire.dtl.DTLVardef@15539e9org.highwire.dtl.DTLVardef@4d17a9org.highwire.dtl.DTLVardef@14c63af_HPS_FORMAT_FIGEXP M_FIG C_FIG Short SummaryThe accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis presents potential molecular mechanisms and therapeutic targets for neurological complications in long-COVID-19 patients.

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