The role of Toll-like receptors and neuroinflammation in Parkinson’s disease

Heidari, Arash; Yazdanpanah, Niloufar; Rezaei, Nima

doi:10.1186/s12974-022-02496-w

Cited by 126 publications

(78 citation statements)

References 155 publications

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“…There is a growing body of evidence supporting a role for TLR4 in Parkinson's disease [55]. TLR4 expression is high in the substantia nigra in association with Parkinson's disease, along with upregulation of the inflammatory cytokine IL-1β [56].…”

Section: Cd16+ Monocytes and Toll Like Receptormentioning

confidence: 99%

SARS-CoV-2 Spike Protein in the Pathogenesis of Prion-like Diseases

Seneff

Kyriakopoulos²,

Nigh

et al. 2022

Preprint

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Human prion protein and prion-like protein misfolding are widely recognized as playing a causal role in a large and growing number of neurodegenerative diseases. Here we summarize the compelling evidence that the spike protein of SARS-CoV-2 contains extended amino acid sequences previously established as characteristic of a prion-like protein. This suggests that vaccine-induced spike protein production is synonymous with production of a prion-like protein, and we trace some of the various pathways through which these proteins should be expected to traverse and distribute throughout the body. We describe some of the highly concerning biological consequences that would be expected to occur with increased frequency as a consequence. Specifically, we describe spike-protein contribution, via its prion-like properties, to neuroinflammation and neurodegenerative diseases; to clotting disorders within the vasculature; to suppressed prion protein regulation in the context of widely prevalent insulin resistance; and other health complications it could be expected to induce. We explain why these prion-like characteristics are more relevant to vaccine-related mRNA-induced spike proteins than natural infection with SARS-CoV-2. We conclude with some potentially ominous public health implications and recommendations for investigations of these possibilities.

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Section: Cd16+ Monocytes and Toll Like Receptormentioning

confidence: 99%

SARS-CoV-2 Spike Protein in the Pathogenesis of Prion-like Diseases

Seneff

Kyriakopoulos²,

Nigh

et al. 2022

Preprint

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“…Its activation triggers the host in ammatory response and the proin ammatory factors, including TNF-α, IL-1β, and IL-6 [47,48,49]. These ndings revealed that gut microbiota might drive the colonic mucosa immunological activation via the TLR4 signaling pathway, resulting in neuroin ammation and further neurodegeneration in PD [50]. To further explore the mechanism by which CDG exerts neural protection by replenishing the intestinal microbiota of PD mice, we highlighted the relationship of in ammation between the gut and the brain.…”

Section: Discussionmentioning

confidence: 94%

Compound Dihuang Granule Changes Gut Microbiota of MPTP-Induced Parkinson's Disease Mice via Inhibiting TLR4/NF-κB Signaling

Huan

Wang

et al. 2022

Preprint

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Intestinal flora was connected to Parkinson's Disease (PD) pathology. The ancient Chinese medication for PD is Compound Dihuang Granule (CDG), and we found a neuroprotective function in treating the constipation of PD patients. Nevertheless, the mechanism of action still needs to be clarified. We predicted the probable targets of CDG against PD through Traditional Chinese medicine (TCM) network pharmacology and verified the analysis through animal experiments in vivo. The protein-protein interaction (PPI) network analysis screened PD-related genes, including TLR4, TBK1, NF-KB (NF-KB p65), and TNF(TNF-α). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses proved that the NF-κB and toll-like receptor signaling pathways serve a key function in CDG therapy of PD. Molecular docking analysis demonstrated that CDG strongly connected to TLR4/NF-κB. Experiments findings indicated that CDG improved the damage of DA neurons and gut microbial dysbiosis, ameliorated motor impairments, and suppressed the PD-associated inflammation and oxidative stress in mice induced by MPTP. CDG suppressed the inflammatory proteins in the colon and protected the intestinal barrier. Overall, CDG improved gut microbial in PD by blocking the pathway of TLR4/NF-κB.

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“…There is a growing body of evidence supporting the role of TLR4 in PD [ 85 ]. TLR4 expression is high in the substantia nigra in association with PD, along with upregulation of the inflammatory cytokine IL-1β [ 86 ].…”

Section: Reviewmentioning

confidence: 99%

A Potential Role of the Spike Protein in Neurodegenerative Diseases: A Narrative Review

Seneff¹,

Kyriakopoulos²,

Nigh³

et al. 2023

Cureus

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Human prion protein and prion-like protein misfolding are widely recognized as playing a causal role in many neurodegenerative diseases. Based on in vitro and in vivo experimental evidence relating to prion and prion-like disease, we extrapolate from the compelling evidence that the spike glycoprotein of SARS-CoV-2 contains extended amino acid sequences characteristic of a prion-like protein to infer its potential to cause neurodegenerative disease. We propose that vaccine-induced spike protein synthesis can facilitate the accumulation of toxic prion-like fibrils in neurons. We outline various pathways through which these proteins could be expected to distribute throughout the body. We review both cellular pathologies and the expression of disease that could become more frequent in those who have undergone mRNA vaccination. Specifically, we describe the spike protein’s contributions, via its prion-like properties, to neuroinflammation and neurodegenerative diseases; to clotting disorders within the vasculature; to further disease risk due to suppressed prion protein regulation in the context of widely prevalent insulin resistance; and to other health complications. We explain why these prion-like characteristics are more relevant to vaccine-related mRNA-induced spike proteins than natural infection with SARS-CoV-2. We note with an optimism an apparent loss of prion-like properties among the current Omicron variants. We acknowledge that the chain of pathological events described throughout this paper is only hypothetical and not yet verified. We also acknowledge that the evidence we usher in, while grounded in the research literature, is currently largely circumstantial, not direct. Finally, we describe the implications of our findings for the general public, and we briefly discuss public health recommendations we feel need urgent consideration. An earlier version of this article was previously posted to the Authorea preprint server on August 16, 2022.

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The role of Toll-like receptors and neuroinflammation in Parkinson’s disease

Cited by 126 publications

References 155 publications

SARS-CoV-2 Spike Protein in the Pathogenesis of Prion-like Diseases

SARS-CoV-2 Spike Protein in the Pathogenesis of Prion-like Diseases

Compound Dihuang Granule Changes Gut Microbiota of MPTP-Induced Parkinson's Disease Mice via Inhibiting TLR4/NF-κB Signaling

A Potential Role of the Spike Protein in Neurodegenerative Diseases: A Narrative Review

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