Abstract:The aim of this study was to establish a link between periodontal disease and Alzheimer's disease (AD) with a view to identifying the major periodontal disease bacteria (Treponema denticola, Tannerella forsythia, and Porphyromonas gingivalis) and/or bacterial components in brain tissue from 12 h postmortem delay. Our request matched 10 AD cases for tissue from Brains for Dementia Research alongside 10 non-AD age-related controls with similar or greater postmortem interval. We exposed SVGp12, an astrocyte cell … Show more
“…During neurodegenerative processes, it has been hypothesized that a higher concentration of Ca ++ activates citrullination [15] but, P. gingivalis LPS and intact citrulline constitute potential contributory factors [68]. …”
Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer’s disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.
“…During neurodegenerative processes, it has been hypothesized that a higher concentration of Ca ++ activates citrullination [15] but, P. gingivalis LPS and intact citrulline constitute potential contributory factors [68]. …”
Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer’s disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.
“…Porphyromonas gingivalis, a periodontal disease-related bacteria, was found at high frequency in the autopsied brain tissue of patients who died of AD; however, it is not found in normal human brain tissue [26]. This result suggests that said bacteria spread hematogenously into the brain.…”
Periodontal disease is a localized infectious disease caused by periodontal disease-related bacteria, such as Porphyromonas gingivalis. Recently, Periodontal disease is known to cause systemic spread of chronic inflammation and exacerbate lifestyle-related diseases such as ischemic heart disease, diabetes mellitus, and obesity, while the inflammatory response plays a large role in the development of neurodegenerative conditions such as Alzheimer's disease (AD).
“…This is noteworthy since peripheral blood mononuclear cells from periodontitis patients show increased levels of autophagy-related gene expression and high levels of mitochondrial reactive oxygen species, with further increase in LC3 upon stimulation of gingival fibroblasts with P. gingivalis LPS [55]. The ability to dysregulate autophagy in phagocytic cells has implications for development of distant organ inflammatory diseases in which either P. gingivalis or its LPS have been detected or been tested experimentally [56,57]. …”
Lipopolysaccharide (LPS) of Porphyromonas gingivalis exists in at least two known forms, O-LPS and A-LPS. A-LPS shows heterogeneity in which two isoforms designated LPS1,435/1,449 and LPS1,690 appear responsible for tissue-specific immune signalling pathways activation and increased virulence. The modification of lipid A to tetra-acylated1,435/1,449 and/or penta-acylated1,690 fatty acids indicates poor growth conditions and bioavailability of hemin. Hemin protects P. gingivalis from serum resistance and the lipid A serves as a site for its binding. The LPS1,435/1,449 and LPS1,690 isoforms can produce opposite effects on the human Toll-like receptors (TLR) TLR2 and TLR4 activation. This enables P. gingivalis to select the conditions for its entry, survival, and that of its co-habiting species in the host, orchestrating its virulence to control innate immune pathway activation and biofilm dysbiosis. This review describes a number of effects that LPS1,435/1,449 and LPS1,690 can exert on the host tissues such as deregulation of the innate immune system, subversion of host cell autophagy, regulation of outer membrane vesicle production, and adverse effects on pregnancy outcome. The ability to change its LPS1,435/1,449 and/or LPS1,690 composition may enable P. gingivalis to paralyze local pro-inflammatory cytokine production, thereby gaining access to its primary location in periodontal tissue.
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