<i>Porphyromonas gingivalis</i>
            in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

Dominy, Stephen S.; Lynch, Casey; Ermini, Florian; Benedyk, Małgorzata; Marczyk, Agata; Konradi, Andrei W.; Mai, Nguyen; Haditsch, Ursula; Raha, Debasish; Griffin, Christina W.; Holsinger, Leslie J.; Arastu‐Kapur, Shirin; Kaba, Samer E.; Lee, Alexander; Ryder, Mark I.; Potempa, Barbara; Mydel, Piotr; Hellvard, Annelie; Adamowicz, Karina; Hastürk, Hatice; Walker, G.; Reynolds, Eric C.; Faull, Richard L. M.; Curtis, Maurice A.; Dragunow, Mike; Potempa, Jan

doi:10.1126/sciadv.aau3333

Cited by 1,255 publications

(1,454 citation statements)

References 110 publications

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“…COR388 is an irreversible active‐site inhibitor developed to target lysine‐gingipain (Kgp) in the brain of Alzheimer's disease (AD) patients . Kgp is a cysteine protease virulence factor secreted by Porphyromonas gingivalis , a keystone bacterium in the development of periodontal disease .…”

Section: Introductionmentioning

confidence: 99%

“…The secretion of gingipain proteases is part of the asaccharolytic metabolism of P. gingivalis, and the gingipains are known to contribute to dysbiosis, immune pathway induction and dysregulation, chronic inflammation, and cellular toxicity . While P. gingivalis resides in oral biofluids and tissues, it has also been shown to translocate to other tissues where it is associated with disease pathology including atherosclerosis, cancer, arthritis, and AD …”

Section: Introductionmentioning

confidence: 99%

“…Additionally, ongoing moderate to severe periodontal disease has been shown to result in more rapid worsening of cognitive decline in clinical AD patients . We recently identified gingipains and P. gingivalis in the brains of subjects with AD, and brain gingipain levels positively correlated to severity of AD diagnosis and pathology . Mechanistic studies in wild‐type mice demonstrated that oral infection with P. gingivalis results in brain colonization and pathology characteristic of AD, and these effects were blocked or reversed by COR388 …”

Section: Introductionmentioning

confidence: 99%

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Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine‐gingipain inhibitor COR388

Arastu‐Kapur¹,

Mai²,

Raha³

et al. 2020

Pharmacology Res & Perspec

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COR388, a small‐molecule lysine‐gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae, typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine‐gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28‐day dose‐response study, COR388 inhibited the lysine‐gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine‐gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine‐gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine‐gingipain and eliminating P. gingivalis infection in humans.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine‐gingipain inhibitor COR388

Arastu‐Kapur¹,

Mai²,

Raha³

et al. 2020

Pharmacology Res & Perspec

Self Cite

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“…11 Furthermore, antifibrinolytic therapy based on the use of tranexemic acid to block the binding of plasminogen to fibrin can occasionally lead to progressive periodontitis. 23 Although chronic periodontitis is driven by a polymicrobial biofilm on the tooth surface below the gum line, species such as Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia play the most important roles in disease initiation and its progression to tooth loss. 13 Chronic periodontitis, the most severe form of gum disease, involves chronic inflammation that results in the erosion of tooth-supporting tissues, including the periodontal ligament and the alveolar bone.…”

Section: Introductionmentioning

confidence: 99%

Plasmin inhibition by bacterial serpin: Implications in gum disease

et al. 2019

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Tannerella forsythia is a periodontopathogen that expresses miropin, a protease inhibitor in the serpin superfamily. In this study, we show that miropin is also a specific and efficient inhibitor of plasmin; thus, it represents the first proteinaceous plasmin inhibitor of prokaryotic origin described to date. Miropin inhibits plasmin through the formation of a stable covalent complex triggered by cleavage of the Lys 368 -Thr 369 (P2-P1) reactive site bond with a stoichiometry of inhibition of 3.8 and an association rate constant (k ass ) of 3.3 × 10 5 M −1 s −1 . The inhibition of the fibrinolytic activity of plasmin was nearly as effective as that exerted by α 2 -antiplasmin. Miropin also acted in vivo by reducing blood loss in a mice tail bleeding assay. Importantly, intact T. forsythia cells or outer membrane vesicles, both of which carry surface-associated miropin, strongly inhibited plasmin. In intact bacterial cells, the antiplasmin activity of miropin protects envelope proteins from plasmin-mediated degradation. In summary, in the environment of periodontal pockets, which are bathed in gingival crevicular fluid consisting of 70% of blood plasma, an abundance of T. forsythia in the bacterial biofilm can cause local inhibition of fibrinolysis, which could have possible deleterious effects on the tooth-supporting structures of the periodontium. K E Y W O R D Sfibrinolysis, plasmin, periodontitis, serpin, Tannerella forsythia 620 |

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“…The disproportionate host response to pathogen penetration results in a continuous release of proinflammatory mediators and chronic inflammation, characterized by progressive and painless destruction of the tooth‐supporting apparatus. Untreated periodontitis may contribute to and even be interrelated with serious systemic diseases, such as cardiovascular diseases, respiratory diseases, diabetes mellitus, rheumatoid arthritis (Hajishengallis, ) and Alzheimer's disease (Dominy et al, ).…”

Section: Introductionmentioning

confidence: 99%

Towards the nano‐control of periodontal inflammation?

et al. 2019

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Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

Abstract: Gingipains from Porphyromonas gingivalis drive Alzheimer’s pathology and can be blocked with small-molecule inhibitors.

Cited by 1,255 publications

References 110 publications

Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine‐gingipain inhibitor COR388

Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine‐gingipain inhibitor COR388

Plasmin inhibition by bacterial serpin: Implications in gum disease

Towards the nano‐control of periodontal inflammation?

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