<i>Porphyromonas gingivalis</i> and Alzheimer disease: Recent findings and potential therapies

Ryder, Mark I.

doi:10.1002/jper.20-0104

Cited by 57 publications

(49 citation statements)

References 34 publications

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“…It is worth noting that recent epidemiological studies have identified a strong association between the periodontal pathogen P. gingivalis and neurodegeneration. P. gingivalis has been detected in the brain autopsy and CSF of individuals diagnosed with AD ( Ryder, 2020 ). Another recent study demonstrated the presence of P. gingivalis -derived lipopolysaccharides in brain samples from AD patients ( Poole et al, 2013 ) and the presence of gingipains, a class of P. gingivalis proteases, in neurons, tau tangles, and Aβ of individuals with AD ( Dominy et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Top-Down Proteomics of Human Saliva Highlights Anti-inflammatory, Antioxidant, and Antimicrobial Defense Responses in Alzheimer Disease

et al. 2021

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Alzheimer disease (AD) is the most prevalent neurodegenerative disease in the elderly, characterized by accumulation in the brain of misfolded proteins, inflammation, and oxidative damage leading to neuronal cell death. By considering the viewpoint that AD onset and worsening may be influenced by environmental factors causing infection, oxidative stress, and inflammatory reaction, we investigated the changes of the salivary proteome in a population of patients with respect to that in healthy controls (HCs). Indeed, the possible use of saliva as a diagnostic tool has been explored in several oral and systemic diseases. Moreover, the oral cavity continuously established adaptative and protective processes toward exogenous stimuli. In the present study, qualitative/quantitative variations of 56 salivary proteoforms, including post-translationally modified derivatives, have been analyzed by RP-HPLC-ESI-IT-MS and MS/MS analyses, and immunological methods were applied to validate MS results. The salivary protein profile of AD patients was characterized by significantly higher levels of some multifaceted proteins and peptides that were either specific to the oral cavity or also expressed in other body districts: (i) peptides involved in the homeostasis of the oral cavity; (ii) proteins acting as ROS/RNS scavengers and with a neuroprotective role, such as S100A8, S100A9, and their glutathionylated and nitrosylated proteoforms; cystatin B and glutathionylated and dimeric derivatives; (iii) proteins with antimicrobial activity, such as α-defensins, cystatins A and B, histatin 1, statherin, and thymosin β4, this last with a neuroprotective role at the level of microglia. These results suggested that, in response to injured conditions, Alzheimer patients established defensive mechanisms detectable at the oral level. Data are available via ProteomeXchange with identifier PXD021538.

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Section: Discussionmentioning

confidence: 99%

Top-Down Proteomics of Human Saliva Highlights Anti-inflammatory, Antioxidant, and Antimicrobial Defense Responses in Alzheimer Disease

et al. 2021

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“…This exciting finding is potentially a major breakthrough for therapy based on low molecular weight small-molecules designed to block the toxic effects of the different types of gingipains secreted by P. gingivalis , which are currently in Phase III clinical trials. An aspect of the gingipains inhibitor COR388 based therapy is provided elsewhere [ 56 ].…”

Section: P Gingivalis Gingipains: the Most Critical Virulenmentioning

confidence: 99%

Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer’s Disease

Kanagasingam

Chukkapalli

Welbury

et al. 2020

Journal of Alzheimer's Disease Reports

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Porphyromonas gingivalis (P. gingivalis) is one of the several important bacterial pathogens associated with the sporadic Alzheimer’s disease (AD). Different serotypes are either capsulated or are non-capsulated. It has been demonstrated that P. gingivalis (non-capsulated) can reproduce the neurodegenerative AD-like changes in vitro, and a capsular P. gingivalis (strain W83) could reproduce the cardinal hallmark lesions of AD in a wild-type mouse model. All P. gingivalis forms express proteolytically active proteases that enable cleavage of the amyloid-β protin precursor (AβPP) and tau resulting in the formation of amyloid-β and neurofibrillary tangles. Tau is an established substrate for gingipains, which can cleave tau into various peptides. Some of the P. gingivalis fragmented tau protein peptides contain “VQIINK” and “VQIVYK” hexapeptide motifs which map to the flanking regions of the microtubule binding domains and are also found in paired helical filaments that form NFTs. P. gingivalis can induce peripheral inflammation in periodontitis and can also initiate signaling pathways that activate kinases, which in turn, phosphorylate neuronal tau. Periodontal disease related inflammation has metabolic implications for an individual’s peripheral and brain health as patients suffering from generalized periodontitis often have related co-morbidities and are “at risk” of developing AD. The aim here is to discuss the role of P. gingivalis behind such associations with the backdrop of huge efforts to test P. gingivalis virulence factors clinically (GAIN Trial: Phase 2/3 Study of COR388 in Subjects with AD) with inhibitors, which may lead to an intervention by reducing the pathogenic bacterial load.

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“…Dominy et al 8 suggested that “gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau” and thus exacerbating amyloid plaque formation, a key factor of Alzheimer disease development. While they reported exciting outcomes concerning the inhibition of gingipains 46 , a group of cysteine proteinases, controlling them in the brain could be a challenging endeavor and may require continuous treatments. Furthermore, the origin of gingipains in human brain needs further clarification.…”

Section: Discussionmentioning

confidence: 99%

A proline rich protein from the gingival seal around teeth exhibits antimicrobial properties against Porphyromonas gingivalis

Fouillen

Mary

Ponce

et al. 2021

Sci Rep

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The gingival seal around teeth prevents bacteria from destroying the tooth-supporting tissues and disseminating throughout the body. Porphyromonas gingivalis, a major periodontopathogen, degrades components of the specialized extracellular matrix that mediates attachment of the gingiva to the tooth. Of these, secretory calcium-binding phosphoprotein proline-glutamine rich 1 (SCPPPQ1) protein has a distinctive resistance to degradation, suggesting that it may offer resistance to bacterial attack. In silico analysis of its amino acid sequence was used to explore its molecular characteristics and to predict its two- and three-dimensional structure. SCPPPQ1 exhibits similarities with both proline-rich and cationic antimicrobial proteins, suggesting a putative antimicrobial potential. A combination of imaging approaches showed that incubation with 20 μM of purified SCPPPQ1 decrease bacterial number (p < 0.01). Fluorescence intensity decreased by 70% following a 2 h incubation of Porphyromonas gingivalis with the protein. Electron microscopy analyses revealed that SCPPPQ1 induced bacterial membrane disruption and breaches. While SCPPPQ1 has no effect on mammalian cells, our results suggest that it is bactericidal to Porphyromonas gingivalis, and that this protein, normally present in the gingival seal, may be exploited to maintain a healthy seal and prevent systemic dissemination of bacteria.

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Porphyromonas gingivalis and Alzheimer disease: Recent findings and potential therapies

Cited by 57 publications

References 34 publications

Top-Down Proteomics of Human Saliva Highlights Anti-inflammatory, Antioxidant, and Antimicrobial Defense Responses in Alzheimer Disease

Top-Down Proteomics of Human Saliva Highlights Anti-inflammatory, Antioxidant, and Antimicrobial Defense Responses in Alzheimer Disease

Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer’s Disease

A proline rich protein from the gingival seal around teeth exhibits antimicrobial properties against Porphyromonas gingivalis

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