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Cited by 372Alzheimer's disease research and treatmentsOral microbiology and periodontitis researchNeuroinflammation and Neurodegeneration Mechanisms

Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice

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Ilievski, Vladimir, Zuchowska, Paulina K., Green, Stefan J., Toth, Peter T., Ragozzino, Michael E., Le, Khuong, Aljewari, Haider W., O’Brien-Simpson, Neil M. +2 more·2018·PLOS ONE
DOI 10.1371/journal.pone.0204941PMC PMC6169940
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Abstract

BACKGROUND: The results from cross sectional and longitudinal studies show that periodontitis is closely associated with cognitive impairment (CI) and Alzhemer's Disease (AD). Further, studies using animal model of periodontitis and human post-mortem brain tissues from subjects with AD strongly suggest that a gram-negative periodontal pathogen, Porphyromonas gingivalis (Pg) and/or its product gingipain is/are translocated to the brain. However, neuropathology resulting from Pg oral application is not known. In this work, we tested the hypothesis that repeated exposure of wild type C57BL/6 mice to orally administered Pg results in neuroinflammation, neurodegeneration, microgliosis, astrogliosis and formation of intra- and extracellular amyloid plaque and neurofibrillary tangles (NFTs) which are pathognomonic signs of AD. METHODS: Experimental chronic periodontitis was induced in ten wild type 8-week old C57BL/6 WT mice by repeated oral application (MWF/week) of Pg/gingipain for 22 weeks (experimental group). Another 10 wild type 8-week old C57BL/6 mice received vehicle alone (control group) MWF per week for 22 weeks. Brain tissues were collected and the presence of Pg/gingipain was determined by immunofluorescence (IF) microscopy, confocal microscopy, and quantitative PCR (qPCR). The hippocampi were examined for the signs of neuropathology related to AD: TNFα, IL1β, and IL6 expression (neuroinflammation), NeuN and Fluoro Jade C staining (neurodegeneration) and amyloid beta1-42 (Aβ42) production and phosphorylation of tau protein at Ser396 were assessed by IF and confocal microscopy. Further, gene expression of amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1), a disintegrin and metalloproteinase domain-containing protein10 (ADAM10) for α-secretase and presenilin1 (PSEN1) for ɣ-secretase, and NeuN (rbFox3) were determined by RT-qPCR. Microgliosis and astrogliosis were also determined by IF microscopy. RESULTS: Pg/gingipain was detected in the hippocampi of mice in the experimental group by immunohistochemistry, confocal microscopy, and qPCR confirming the translocation of orally applied Pg to the brain. Pg/gingipain was localized intra-nuclearly and peri-nuclearly in microglia (Iba1+), astrocytes (GFAP+), neurons (NeuN+) and was evident extracellularly. Significantly greater levels of expression of IL6, TNFα and IL1β were evident in experimental as compared to control group (p<0.01, p<0.00001, p<0.00001 respectively). In addition, microgliosis and astrogliosis were evident in the experimental but not in control group (p <0.01, p<0.0001 respectively). Neurodegeneration was evident in the experimental group based on a fewer number of intact neuronal cells assessed by NeuN positivity and rbFOX3 gene expression, and there was a greater number of degenerating neurons in the hippocampi of experimental mice assessed by Fluoro Jade C positivity. APP and BACE1 gene expression were increased in experimental group compared with control group (p<0.05, p<0.001 respectively). PSEN1 gene expression was higher in experimental than control group but the difference was not statistically significant (p = 0.07). ADAM10 gene expression was significantly decreased in experimental group compared with control group (p<0.01). Extracellular Aβ42 was detected in the parenchyma in the experimental but not in the control group (p< 0.00001). Finally, phospho-Tau (Ser396) protein was detected and NFTs were evident in experimental but not in the control group (p<0.00001). CONCLUSIONS: This study is the first to show neurodegeneration and the formation of extracellular Aβ42 in young adult WT mice after repeated oral application of Pg. The neuropathological features observed in this study strongly suggest that low grade chronic periodontal pathogen infection can result in the development of neuropathology that is consistent with that of AD.

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  • There is a large increase in bacterial load and bacterial species in Alzheimer's disease brains, including Porphyromonas gingivalis, which can live intracellularly in glia and neurons.

    “There is a large increase in bacterial load and bacterial species in AD brains [79, 90], including P. gingivalis, which can live intracellularly in glia and neurons [91].”

    From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [91]

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  1. [51]Little CS, Joyce TA, Hammond CJ, Matta H, Cahn D, Appelt DM, et al Detection of bacterial antigens and Alzheimer's disease-like pathology in the central nervous system of BALB/c mice following intranasal infection with a laboratory isolate of Chlamydia pneumoniae. Front Aging Neurosci. 2014; 6: 304 10.3389/fnagi.2014.00304 25538615 PMC4257355 · DOI · Paper page

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Authors
Ilievski, V., Zuchowska, P. K., Green, S. J., Toth, P. T., Ragozzino, M. E., Le, K., Aljewari, H. W., O’Brien-Simpson, N. M., Reynolds, E. C., & Watanabe, K.
Affiliations
  • University of Illinois Chicago (US)
  • The University of Melbourne (AU)
Corresponding author
Watanabe, Keiko
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2018-10-03
Volume
13
Issue
10
Pages
e0204941
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0204941
PMC
PMC6169940
OpenAlex
W2895374072
Cited by
372
References
74
Citations by year
2026: 40 · 2025: 55 · 2024: 53 · 2023: 48 · 2022: 42 · 2021: 61 · 2020: 51 · 2019: 21 · 2018: 1
FWCI
22.97
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
National Institutes of Health (R01DE021405)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
periodontitis, Porphyromonas gingivalis, gingipains, Alzheimer's disease, neuroinflammation, neurodegeneration, amyloid-beta, tau phosphorylation, microglial activation, astrocyte activation, amyloid plaques, neurofibrillary tangles, hippocampus, APP processing, BACE1, ADAM10
MeSH terms
ADAM10 Protein, Administration, Oral, Alzheimer Disease, Animals, Astrocytes, Cell Count, Cross-Sectional Studies, DNA-Binding Proteins, Encephalitis, Frontal Lobe, Gene Expression Regulation, Hippocampus, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Peptide Fragments, Periodontitis, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, tau Proteins, Porphyromonas gingivalis, Microglia, Intracellular Space, Mice, Presenilin-1, Amyloid Precursor Protein Secretases, Cognitive Dysfunction

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