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Sci Adv. 2019 Jan 23;5(1):eaau3333. doi: 10.1126/sciadv.aau3333. eCollection 2019 Jan.

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

Author information

1
Cortexyme, Inc., 269 East Grand Ave., South San Francisco, CA, USA.
2
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
3
Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
4
Division of Periodontology, Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA.
5
Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, USA.
6
Broegelman Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.
7
The Forsyth Institute, Cambridge, MA, USA.
8
Harvard University School of Dental Medicine, Boston, MA, USA.
9
Cooperative Research Centre for Oral Health Science, Melbourne Dental School and the Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Melbourne, Victoria, Australia.
10
Department of Anatomy with Radiology, Centre for Brain Research and NeuroValida, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
11
Centre for Brain Research and NeuroValida, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
12
Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
13
Department of Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.

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.

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