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

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 virus's 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 spike's 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.

‘Spikeopathy’: COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA

“…Tillman et al, (2023) [ 172 ] described how the co-expression of the S1 and S2 subunits of the SARS-CoV-2 spike protein, via a helical motif in the spike neck, causes profound downregulation of functional α7 nAChR, which “is implicated in neuropsychiatric diseases and disrupts the cholinergic anti-inflammatory pathway” (p. 689). German researchers [ 173 ] (preprint) autopsied mice that had been intravenously injected with the S1 unit of the spike protein and examined skulls from human autopsies. They found the S1 unit binding to cells in most organs, including ovaries and testes.…”

“…In addition to experimentally injecting mice with the S1 unit of spike protein, they autopsied 34 patients who died from non-COVID-19 illnesses and found 10 of them had persisting spike proteins in their skulls and noted these might be involved in long COVID symptoms via their spread via the meninges into the brain parenchyma. In summary, the spike protein accumulates in various regions of the brain, persists there even after death, and causes activation of microglia, blocking of α 7 nAChR and dysregulation of coagulation- and neutrophil-related pathways as well as upregulation of inflammatory proteins, all of which are connected to memory loss, inflammation of the brain and cell death [ 173 ].…”

In Silico Analyses Indicate a Lower Potency for Dimerization of TLR4/MD-2 as the Reason for the Lower Pathogenicity of Omicron Compared to Wild-Type Virus and Earlier SARS-CoV-2 Variants

“…The correlation between TLR4 dimerization and activation with pathogenicity of the SARS-CoV-2 variants indicate TLR4 as a potential therapeutic target for treatment of COVID-19. While so far there are no FDA approved TLR4 antagonists available, intensive research [106] on TLR4 as a therapeutic target is ongoing, with emphasis on respiratory and neurological complications of SARS-CoV-2 [107], also with respect to accumulating data for long-term nervous system consequences after COVID-19 [108,109]. Beside various TLR4 antagonists which inhibit binding to or dimerization of TLR4, also inhibitors of the downstream signaling pathways, including inhibitors of the NF-κB pathway, are promising targets for therapeutic intervention [50,51].…”

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis

“…Endothelial injury can result from direct infection by SARS-CoV-2 causing endothelial cell apoptosis and endotheliitis as well as subsequent systemic inflammatory responses [33,34,37,39,49,51,52]. The spike protein alone can induce neuronal injury [53], destabilise microvascular haemostasis [54], induce thrombosis [55], (irreversibly) activate platelets [56][57][58] and impair endothelial function [43,59], with some effects independent of ACE2 [60] or possibly from anti-spike antibodies [61]. With endothelial dysfunction comes impaired vascular tone and a prothrombotic state [32,34,35,37,43,49].…”