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Source: http://advances.sciencemag.org/conte.../eaau3333.full
Porphyromonas gingivalis in Alzheimer?s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors
Stephen S. Dominy1,*,?, Casey Lynch1,*, Florian Ermini1, Malgorzata Benedyk2,3, Agata Marczyk2, Andrei Konradi1, Mai Nguyen1, Ursula Haditsch1, Debasish Raha1, Christina Griffin1, Leslie J. Holsinger1, Shirin Arastu-Kapur1, Samer Kaba1, Alexander Lee1, Mark I. Ryder4, Barbara Potempa5, Piotr Mydel2,6, Annelie Hellvard3,6, Karina Adamowicz2, Hatice Hasturk7,8, Glenn D. Walker9, Eric C. Reynolds9, Richard L. M. Faull10, Maurice A. Curtis11,12, Mike Dragunow11,13 and Jan Potempa2,5,*
Science Advances 23 Jan 2019:
Vol. 5, no. 1, eaau3333
DOI: 10.1126/sciadv.aau3333
Abstract
Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer?s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer?s patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1?42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1?42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer?s disease...
Porphyromonas gingivalis in Alzheimer?s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors
Stephen S. Dominy1,*,?, Casey Lynch1,*, Florian Ermini1, Malgorzata Benedyk2,3, Agata Marczyk2, Andrei Konradi1, Mai Nguyen1, Ursula Haditsch1, Debasish Raha1, Christina Griffin1, Leslie J. Holsinger1, Shirin Arastu-Kapur1, Samer Kaba1, Alexander Lee1, Mark I. Ryder4, Barbara Potempa5, Piotr Mydel2,6, Annelie Hellvard3,6, Karina Adamowicz2, Hatice Hasturk7,8, Glenn D. Walker9, Eric C. Reynolds9, Richard L. M. Faull10, Maurice A. Curtis11,12, Mike Dragunow11,13 and Jan Potempa2,5,*
Science Advances 23 Jan 2019:
Vol. 5, no. 1, eaau3333
DOI: 10.1126/sciadv.aau3333
Abstract
Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer?s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer?s patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1?42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1?42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer?s disease...