236
views
1
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

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

          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.

          Related collections

          Most cited references84

          • Record: found
          • Abstract: found
          • Article: not found

          Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

          The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The evolution of preclinical Alzheimer's disease: implications for prevention trials.

            As the field begins to test the concept of a "preclinical" stage of neurodegenerative disease, when the pathophysiological process has begun in the brain, but clinical symptoms are not yet manifest, a number of intriguing questions have already arisen. In particular, in preclinical Alzheimer's disease (AD), the temporal relationship of amyloid markers to markers of neurodegeneration and their relative utility in the prediction of cognitive decline among clinically normal older individuals remains to be fully elucidated. Secondary prevention trials in AD have already begun in both genetic at-risk and amyloid at-risk cohorts, with several more trials in the planning stages, and should provide critical answers about whether intervention at this very early stage of disease can truly bend the curve of clinical progression. This review will highlight recent progress in cognitive, imaging, and biomarker outcomes in the field of preclinical AD, and the remaining gaps in knowledge.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease

              Background Interleukin-1 beta (IL-1β) and its key regulator, the inflammasome, are suspected to play a role in the neuroinflammation observed in Alzheimer’s disease (AD); no conclusive data are nevertheless available in AD patients. Results mRNA for inflammasome components (NLRP1, NLRP3, PYCARD, caspase 1, 5 and 8) and downstream effectors (IL-1β, IL-18) was up-regulated in severe and MILD AD. Monocytes co-expressing NLRP3 with caspase 1 or caspase 8 were significantly increased in severe AD alone, whereas those co-expressing NLRP1 and NLRP3 with PYCARD were augmented in both severe and MILD AD. Activation of the NLRP1 and NLRP3 inflammasomes in AD was confirmed by confocal microscopy proteins co-localization and by the significantly higher amounts of the pro-inflammatory cytokines IL-1β and IL-18 being produced by monocytes. In MCI, the expression of NLRP3, but not the one of PYCARD or caspase 1 was increased, indicating that functional inflammasomes are not assembled in these individuals: this was confirmed by lack of co-localization and of proinflammatory cytokines production. Conclusions The activation of at least two different inflammasome complexes explains AD-associated neuroinflammation. Strategies targeting inflammasome activation could be useful in the therapy of AD.
                Bookmark

                Author and article information

                Journal
                Sci Adv
                Sci Adv
                SciAdv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                January 2019
                23 January 2019
                : 5
                : 1
                : eaau3333
                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.
                Author notes
                [*]

                These authors contributed equally to this work as co-senior authors.

                []Corresponding author. Email: sdominy@ 123456cortexyme.com
                Author information
                http://orcid.org/0000-0002-0816-9658
                http://orcid.org/0000-0002-0176-8180
                http://orcid.org/0000-0003-4304-4380
                http://orcid.org/0000-0003-4799-5044
                http://orcid.org/0000-0002-8540-4017
                http://orcid.org/0000-0002-1226-6952
                http://orcid.org/0000-0001-5289-9810
                http://orcid.org/0000-0002-6618-4856
                http://orcid.org/0000-0002-3600-7461
                Article
                aau3333
                10.1126/sciadv.aau3333
                6357742
                30746447
                0abb510f-ae2e-4506-9c70-87162410a4a5
                Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 May 2018
                : 11 December 2018
                Funding
                Funded by: Cortexyme, Inc.;
                Award ID: N/A
                Categories
                Research Article
                Research Articles
                SciAdv r-articles
                Diseases and Disorders
                Neuroscience
                Health and Medicine
                Custom metadata
                Eunice Ann Alesin

                Comments

                Comment on this article