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

被引：1485

作者：

Dominy, Stephen S. ^{[1
]}

Lynch, Casey ^{[1
]}

Ermini, Florian ^{[1
]}

Benedyk, Malgorzata ^{[2
,3
]}

Marczyk, Agata ^{[2
]}

Konradi, Andrei ^{[1
]}

Nguyen, Mai ^{[1
]}

Haditsch, Ursula ^{[1
]}

Raha, Debasish ^{[1
]}

Griffin, Christina ^{[1
]}

Holsinger, Leslie J. ^{[1
]}

Arastu-Kapur, Shirin ^{[1
]}

Kaba, Samer ^{[1
]}

Lee, Alexander ^{[1
]}

Ryder, Mark I. ^{[4
]}

Potempa, Barbara ^{[5
]}

Mydel, Piotr ^{[2
,6
]}

Hellvard, Annelie ^{[3
,6
]}

Adamowicz, Karina ^{[2
]}

Hasturk, Hatice ^{[7
,8
]}

Walker, Glenn D. ^{[9
,10
]}

Reynolds, Eric C. ^{[9
,10
]}

Faull, Richard L. M. ^{[11
]}

Curtis, Maurice A. ^{[12
,13
]}

Dragunow, Mike ^{[12
,14
]}

Potempa, Jan ^{[2
,5
]}

机构：

[1] Cortexyme Inc, 269 East Grand Ave, San Francisco, CA 94080 USA

[2] Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Dept Microbiol, Krakow, Poland

[3] Jagiellonian Univ, Malopolska Ctr Biotechnol, Krakow, Poland

[4] Univ Calif San Francisco, Dept Orofacial Sci, Div Periodontol, San Francisco, CA 94143 USA

[5] Univ Louisville, Sch Dent, Dept Oral Immunol & Infect Dis, Louisville, KY 40292 USA

[6] Univ Bergen, Dept Clin Sci, Broegelman Res Lab, Bergen, Norway

[7] Forsyth Inst, Cambridge, MA USA

[8] Harvard Univ, Sch Dent Med, 188 Longwood Ave, Boston, MA 02115 USA

[9] Univ Melbourne, Melbourne Dent Sch, Cooperat Res Ctr Oral Hlth Sci, Melbourne, Vic, Australia

[10] Univ Melbourne, Bio21 Inst Mol Sci & Biotechnol, Melbourne, Vic, Australia

[11] Univ Auckland, Ctr Brain Res & NeuroValida, Dept Anat Radiol, Fac Med & Hlth Sci, Auckland, New Zealand

[12] Univ Auckland, Fac Med & Hlth Sci, Ctr Brain Res & NeuroValida, Auckland, New Zealand

[13] Univ Auckland, Fac Med & Hlth Sci, Dept Anat & Med Imaging, Auckland, New Zealand

[14] Univ Auckland, Dept Pharmacol, Fac Med & Hlth Sci, Auckland, New Zealand

来源：

SCIENCE ADVANCES | 2019年 / 5卷 / 01期

关键词：

REAL-TIME PCR; ACTINOBACILLUS-ACTINOMYCETEMCOMITANS; CEREBROSPINAL-FLUID; VIRULENCE FACTORS; EPITHELIAL-CELLS; ARG-GINGIPAIN; TOOTH LOSS; TAU; BACTERIA; INFECTION;

D O I：

10.1126/sciadv.aau3333

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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 A. 1-42, 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 A. 1-42 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.

引用

页数：21

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