Mitogen Activated Protein Kinase (MAPK) Activation, p53, and Autophagy Inhibition Characterize the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein Induced Neurotoxicity

"Conclusions: In this article, we have reviewed the research literature on the spike protein-related processes that lead to the development of neurodegenerative disease, in the context of several recent papers reporting on the observed mechanisms of toxicity. We were initially motivated by the observation that COVID-19 patients often suffer from long-term sequelae that include cognitive impairment -- so-called long-haul COVID disease. There is also a post-vaccination syndrome that strongly resembles long COVID.

Central to the promotion of prion and prion-like disease is the induction of γ-secretase metabolism of the APP [amyloid precursor protein] sequence, which, through BACE-1 [β-site APP cleaving enzyme 1], yields the AIDC [APP intracellular domain] sequence, a highly potent transcriptional activator of the TP53 gene. This disease-prone metabolic state is induced through p38 MAPK [mitogen-activated protein kinase] activation in neurons. Therefore, the SARS-CoV-2 spike protein can be a re-enforcing toxicity factor, since it induces both p38 MAPK and JNK [c-Jun N-terminal kinase] activation which subsequently will provide a surplus of activated p53...

We propose that age-related impairments in autophagy may predispose towards increased risk to cognitive issues associated with the ability of the spike protein to behave as a prion-like protein, triggering misfolding of PrP and other amyloidogenic proteins. The spike protein has been shown to induce an inflammatory response in microglia, which can lead to oxidative stress and DNA damage. Through MAPK activation via TLR4 receptors, as well as JNK activation, the spike protein can be expected to suppress key phosphatases that normally would restore cellular homeostasis following p53 activation via MAPK. Sustained p53 phosphorylation in neurons can induce PrPC [cellular prion protein] conversion to PrPSC [scrapie isoform of the prion protein]. The precipitation of misfolded PrP [prion protein] into fibrils causes a loss-of-function pathology, and subsequent catastrophic autophagy failure ultimately leads to programmed cell death (apoptosis) and resulting neurological symptoms and accelerated senescence.

Our work has important implications for public policy given the continued widespread application of COVID-19 vaccines. If the spike protein conceivably could contribute to future neurodegenerative diseases, then the risk-benefit calculation for mass indiscriminate vaccination should be re-examined. If the arguments presented here are found to be true, the vaccinated population has already been subjected to a great deal of harm."