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

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

doi:10.1126/sciadv.aau3333

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

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

Authors

Stephen S Dominy¹, Casey Lynch¹, Florian Ermini¹, Malgorzata Benedyk^{2

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 Mydel^{2

6}, Annelie Hellvard^{3

6}, Karina Adamowicz², Hatice Hasturk^{7

8}, Glenn D Walker⁹, Eric C Reynolds⁹, Richard L M Faull¹⁰, Maurice A Curtis^{11

12}, Mike Dragunow^{11

13}, Jan Potempa^{2

5}

Affiliations

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 Aβ_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 Aβ_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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / cerebrospinal fluid
Alzheimer Disease / drug therapy*
Alzheimer Disease / microbiology*
Alzheimer Disease / pathology
Amyloid beta-Peptides / metabolism
Animals
Bacteroidaceae Infections / drug therapy*
Bacteroidaceae Infections / microbiology
Brain / microbiology*
Brain / pathology*
Cell Line, Tumor
Disease Models, Animal
Female
Gingipain Cysteine Endopeptidases / antagonists & inhibitors
Gingipain Cysteine Endopeptidases / metabolism
Gingipain Cysteine Endopeptidases / pharmacology
Humans
Male
Mice
Mice, Inbred BALB C
Middle Aged
Neuroprotective Agents / pharmacology
Neuroprotective Agents / therapeutic use*
Peptide Fragments / metabolism
Pilot Projects
Porphyromonas gingivalis / drug effects
Porphyromonas gingivalis / enzymology*
Porphyromonas gingivalis / genetics
Prospective Studies
Saliva / microbiology
Small Molecule Libraries / pharmacology
Small Molecule Libraries / therapeutic use*
tau Proteins / metabolism

Substances

Amyloid beta-Peptides
Gingipain Cysteine Endopeptidases
MAPT protein, human
Neuroprotective Agents
Peptide Fragments
Small Molecule Libraries
amyloid beta-protein (1-42)
tau Proteins

Grants and funding

R01 DE022597/DE/NIDCR NIH HHS/United States