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

Ilievski, Vladimir ; Zuchowska, Paulina K ; Green, Stefan J ; Toth, Peter T ; Ragozzino, Michael E ; Le, Khuong ; Aljewari, Haider W ; O'Brien-Simpson, Neil M ; Reynolds, Eric C ; Watanabe, Keiko Lakshmana, Madepalli K.

PloS one, 2018-10, Vol.13 (10), p.e0204941-e0204941 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice
Autor: Ilievski, Vladimir ; Zuchowska, Paulina K ; Green, Stefan J ; Toth, Peter T ; Ragozzino, Michael E ; Le, Khuong ; Aljewari, Haider W ; O'Brien-Simpson, Neil M ; Reynolds, Eric C ; Watanabe, Keiko
Lakshmana, Madepalli K.
Assuntos: ADAM10 Protein - genetics ; Administration, Oral ; Age ; Alzheimer Disease - genetics ; Alzheimer Disease - metabolism ; Alzheimer Disease - microbiology ; Alzheimer Disease - pathology ; Alzheimer's disease ; Alzheimers disease ; Amyloid beta-Peptides - biosynthesis ; Amyloid beta-Peptides - metabolism ; Amyloid beta-protein ; Amyloid precursor protein ; Amyloid Precursor Protein Secretases - genetics ; Anaerobic bacteria ; Animal cognition ; Animals ; Aspartic Acid Endopeptidases - genetics ; Astrocytes ; Astrocytes - pathology ; b-Site APP cleaving enzyme 1 ; Biology and Life Sciences ; Brain ; Cell Count ; Chronic infection ; Cognitive ability ; Cognitive Dysfunction - genetics ; Cognitive Dysfunction - metabolism ; Cognitive Dysfunction - microbiology ; Cognitive Dysfunction - pathology ; Confocal microscopy ; Correlation analysis ; Cross-Sectional Studies ; Dementia ; Dentistry ; DNA-Binding Proteins ; Encephalitis - genetics ; Encephalitis - metabolism ; Encephalitis - microbiology ; Encephalitis - pathology ; Frontal Lobe - pathology ; Gender differences ; Gene expression ; Gene Expression Regulation ; Gingipain ; Glial fibrillary acidic protein ; Gliosis ; Gum disease ; Hippocampus ; Hippocampus - metabolism ; Hippocampus - pathology ; Immunofluorescence ; Immunohistochemistry ; Immunology ; Inflammation ; Interleukin 1 ; Interleukin 6 ; Intracellular Space - metabolism ; Longitudinal studies ; Male ; Medicine and Health Sciences ; Mice ; Mice, Inbred C57BL ; Microglia ; Microglia - pathology ; Microscopy ; Nerve Tissue Proteins - metabolism ; Neurodegeneration ; Neurofibrillary tangles ; Neurons ; Neurons - pathology ; Nuclear Proteins - metabolism ; Oral administration ; Pathogens ; Peptide Fragments - biosynthesis ; Peptide Fragments - metabolism ; Periodontics ; Periodontitis - microbiology ; Phosphorylation ; Porphyromonas gingivalis - physiology ; Presenilin-1 - genetics ; Proteins ; Research and Analysis Methods ; Risk factors ; Secretase ; Statistical analysis ; Studies ; tau Proteins - metabolism ; Tissues ; Translocation ; β-Site APP-cleaving enzyme 1
É parte de: PloS one, 2018-10, Vol.13 (10), p.e0204941-e0204941
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Current address: Fluorescence Imaging Core Facility, University of Illinois at Chicago, Chicago, Illinois, United States of America
Competing Interests: The authors have declared that no competing interests exist.
Current address: DNA Core Facility, University of Illinois at Chicago, Chicago, Illinois, United States of America
Descrição: 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. 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. 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). 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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

Ilievski, Vladimir ; Zuchowska, Paulina K ; Green, Stefan J ; Toth, Peter T ; Ragozzino, Michael E ; Le, Khuong ; Aljewari, Haider W ; O'Brien-Simpson, Neil M ; Reynolds, Eric C ; Watanabe, Keiko Lakshmana, Madepalli K.

United States: Public Library of Science

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