Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice

Bojlul Bahar; Shalini Kanagasingam; Murtaza M. Tambuwala; Alaa A.A. Aljabali; Stephanie A. Dillon; Saeid Doaei; Richard Welbury; Sasanka S. Chukkapalli; Sim K. Singhrao

doi:10.3233/jad-210465

journal article Aug 03, 2021

Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice

Bojlul Bahar Shalini Kanagasingam Murtaza M. Tambuwala

Alaa A.A. Aljabali Stephanie A. Dillon Saeid Doaei

Richard Welbury Sasanka S. Chukkapalli Sim K. Singhrao

Journal of Alzheimer’s Disease Vol. 82 No. 3 pp. 1259-1275 · SAGE Publications

View at Publisher Save 10.3233/jad-210465

Abstract

Background: Periodontal disease(s) and metabolic illnesses negatively impact the quality of life and, eventually mental health. Objective: This study investigated the effect of Porphyromonas gingivalis (W83) oral infection on the development of Alzheimer’s disease (AD) pathophysiology in a wild-type obese, diabetic (db/db) mouse model. Methods: The db/db mice were either orally infected with P. gingivalis and Fusobacterium nucleatum or sham infected for 16 weeks. The presence of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) were assessed using a silver impregnation technique and subsequently by immunohistochemistry for tau and neuroinflammation. The mRNA abundance of a panel of 184 genes was performed using quantitative real-time PCR, and the differentially expressed genes were analyzed by Ingenuity Pathway Analysis. Results: While no Aβ plaques and NFTs were evident by silver impregnation, immunohistochemistry (glial cell markers) of the P. gingivalis-infected mice tissue sections exhibited neuroinflammation in the form of reactive microglia and astrocytes. Anti-tau immunopositivity, in addition to cells, was prominent in thickened axons of hippocampal CA neurons. The mRNA abundance of crucial genes in the insulin signaling pathway (INSR, IGF1, IRS, IDE, PIK3R, SGK1, GYS, GSK3B, AKT1) were upregulated, potentially exacerbating insulin resistance in the brain by P. gingivalis oral infection. Increased mRNA abundance of several kinases, membrane receptors, transcription factors, and pro-inflammatory mediators indicated hyperactivation of intracellular cascades with potential for tau phosphorylation and Aβ release in the same infection group. Conclusion: P. gingivalis W83 infection of db/db mice provides a disease co-morbidity model with the potential to reproduce AD pathophysiology with induced periodontal disease.

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References

61

[1]

Chapple "Primary prevention of periodontitis: Managing gingivitis" J Clin Periodontol (2015) 10.1111/jcpe.12366

[2]

How "Porphyromonas gingivalis: An overview of periodontopathic pathogen below the gum line" Front Microbiol (2016) 10.3389/fmicb.2016.00053

[3]

Vernal "Differential cytokine expression by human dendritic cells in response to different porphyromonas gingivalis capsular serotypes" J Clin Periodontol (2009) 10.1111/j.1600-051x.2009.01462.x

[4]

Silver "Experimental transient bacteraemias in human subjects with varying degrees of plaque accumulation and gingival inflammation" J Clin Periodontol (1977) 10.1111/j.1600-051x.1977.tb01888.x

[5]

Païssé "Comprehensive description of blood microbiome from healthy donors assessed by 16S targeted metagenomic sequencing" Transfusion (2016) 10.1111/trf.13477

[6]

DeLeon-Pennell "Circulating Porphyromonas gingivalis lipopolysaccharide resets cardiac homeostasis in mice through a matrix metalloproteinase-9-dependent mechanism" Physiol Rep (2013) 10.1002/phy2.79

[7]

Troseid "Plasma lipopolysaccharide is closely associated with glycemic control and abdominal obesity" Diabetes Care (2013) 10.2337/dc13-0451

[8]

Poole "Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue" J Alzheimers Dis (2013) 10.3233/jad-121918

[9]

Dominy "Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors" Sci Adv (2019) 10.1126/sciadv.aau3333

[10]

Alzheimer "An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”" Clin Anat (1995) 10.1002/ca.980080612

[11]

Veerhuis "Complement in the brain" Mol Immunol (2011) 10.1016/j.molimm.2011.04.003

[12]

Kumar "Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease" Sci Transl Med (2016) 10.1126/scitranslmed.aaf1059

[13]

Eimer "Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection" Neuron (2018) 10.1016/j.neuron.2018.06.030

[14]

Díaz-Zúñiga "Alzheimer’s disease-like pathology triggered by Porphyromonas gingivalis in wild type rats is serotype dependent" Front Immunol (2020) 10.3389/fimmu.2020.588036

[15]

Chaffee "Association between chronic periodontal disease and obesity: A systematic review and meta-analysis" J Periodontol (2010) 10.1902/jop.2010.100321

[16]

Campus "Diabetes and periodontal disease: A case-control study" J Periodontol (2005) 10.1902/jop.2005.76.3.418

[17]

Mysak "Porphyromonas gingivalis: Major periodontopathic pathogen overview" J Immunol Res (2014) 10.1155/2014/476068

[18]

Chiu "Effect of high glucose, Porphyromonas gingivalis lipopolysaccharide and advanced glycation end-products on production of interleukin-6/-8 by gingival fibroblasts" J Periodontal Res (2016) 10.1111/jre.12391

[19]

Murray "Lipopolysaccharide from the periodontal pathogen Porphyromonas gingivalis prevents apoptosis of HL60-derived neutrophils in vitro" Infect Immun (2003) 10.1128/iai.71.12.7232-7235.2003

[20]

Holmes "Role of infection in the pathogenesis of Alzheimer’s disease" CNS Drugs (2009) 10.2165/11310910-000000000-00000

[21]

Marques "Blood-brain-barriers in aging and in Alzheimer’s disease. See comment in PubMed Commons below" Mol Neurodegener (2013) 10.1186/1750-1326-8-38

[22]

van Oijen "Atherosclerosis and risk for dementia" Ann Neurol (2007) 10.1002/ana.21073

[23]

Demmer "Periodontal disease and incident dementia: The Atherosclerosis Risk in Communities Study (ARIC)" Neurology (2020) 10.1212/wnl.0000000000010312

[24]

Dioguardi "The role of periodontitis and periodontal bacteria in the onset and progression of Alzheimer’s disease: A systematic review" J Clin Med (2020) 10.3390/jcm9020495

[25]

Li "Diabetes mellitus increases risk of incident dementia in APOEɛ4 carriers: A meta-analysis. L" J Alzheimers Dis (2020) 10.3233/jad-191068

[26]

Cole "The distribution of amyloid plaques in the cerebellum and brain stem in Down’s syndrome and Alzheimer’s disease: A light microscopical analysis" Acta Neuropathol (1993) 10.1007/bf00230495

[27]

Bahar "An evaluation of the molecular mode of action of trans-resveratrol in the Porphyromonas gingivalis lipopolysaccharide challenged neuronal cell model" Mol Biol Rep (2021) 10.1007/s11033-020-06024-y

[28]

DAVID: Database for Annotation, Visualization, and Integrated Discovery

Glynn Dennis, Brad T Sherman, Douglas A Hosack et al.

Genome Biology 2003 10.1186/gb-2003-4-5-p3

[29]

Ilievski "Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice" PLoS One (2018) 10.1371/journal.pone.0204941

[30]

Stein "Tooth loss, dementia and neuropathy in the Nun study" J Am Dent Assoc (2007) 10.14219/jada.archive.2007.0046

[31]

Pandini "Insulin has multiple antiamyloidogenic effects on human neuronal cells" Endocrinology (2013) 10.1210/en.2012-1661

[32]

Cholerton "Insulin, cognition, and dementia" Eur J Pharmacol (2013) 10.1016/j.ejphar.2013.08.008

[33]

Poole "Active infection of Porphorymonas gingivalis and infection-induced complement activation in ApoE-/-mice brains" J Alzheimers Dis (2015) 10.3233/jad-140315

[34]

Dunn "An association between dementia and infectious disease: Evidence from a case-control study" Alzheimer Dis Assoc Disord (2005) 10.1097/01.wad.0000165511.52746.1f

[35]

Holmes "Systemic infection, interleukin 1beta and cognitive decline in Alzheimer’s disease" Neurol Neurosurg Psychiatry (2003) 10.1136/jnnp.74.6.788

[36]

Jope "Stressed and inflamed, can GSK3 be blamed?" Trends Biochem Sci (2017) 10.1016/j.tibs.2016.10.009

[37]

Spinelli "Brain insulin resistance and hippocampal plasticity: Mechanisms and biomarkers of cognitive decline" Front Neurosci (2019) 10.3389/fnins.2019.00788

[38]

Meloni "GLP-1 receptor activated insulin secretion from pancreatic β-cells: Mechanism and glucose dependence" Diabetes Obes Metab (2013) 10.1111/j.1463-1326.2012.01663.x

[39]

Fu "Brain endothelial cells regulate glucagon-like peptide 1 entry into the brain via a receptor-mediated process" Front Physiol (2020) 10.3389/fphys.2020.00555

[40]

Knauf "Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage" J Clin Invest (2005) 10.1172/jci25764

[41]

Sandoval "Brain GLP-1 and insulin sensitivity" Mol Cell Endocrinol (2015) 10.1016/j.mce.2015.02.017

[42]

Kuwabara "Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb" EMBO Mol Med (2011) 10.1002/emmm.201100177

[43]

Bedse "Aberrant insulin signaling in Alzheimer’s disease: Current knowledge" Front Neurosci (2015) 10.3389/fnins.2015.00204

[44]

Li "Link between type 2 diabetes and Alzheimer’s disease: From epidemiology to mechanism and treatment" Clin Interv Aging (2015) 10.2147/cia.s74042

[45]

de la Monte "The full spectrum of Alzheimer’s disease is rooted in metabolic derangements that drive type 3 diabetes" Adv Exp Med Biol (2019) 10.1007/978-981-13-3540-2_4

[46]

Silha "Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice" Am J Physiol Endocrinol Metab (2002) 10.1152/ajpendo.00014.2002

[47]

Yarchoan "Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies" Acta Neuropathol (2014) 10.1007/s00401-014-1328-5

[48]

Xu "Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours" Cell Biosci (2020) 10.1186/s13578-020-00416-0

[49]

Gabbouj "Altered insulin signaling in Alzheimer’s disease brain - Special emphasis on PI3K-Akt Pathway" Front Neurosci (2019) 10.3389/fnins.2019.00629

[50]

Antico Arciuch "Akt1 intramitochondrial cycling is a crucial step in the redox modulation of cell cycle progression" PLoS One (2009) 10.1371/journal.pone.0007523

Showing 50 of 61 references

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References

Details

Published: Aug 03, 2021
Vol/Issue: 82(3)
Pages: 1259-1275

Authors

B

Bojlul Bahar

Nutrition Sciences and Applied Food Safety Studies, Research Centre for Global Development, School of Sport & Health Sciences, University of Central Lancashire, Preston, UK

S

Shalini Kanagasingam

Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK

M

Murtaza M. Tambuwala

School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, Northern Ireland, UK

A

Alaa A.A. Aljabali

Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan

S

Stephanie A. Dillon

Nutrition Sciences and Applied Food Safety Studies, Research Centre for Global Development, School of Sport & Health Sciences, University of Central Lancashire, Preston, UK

S

Saeid Doaei

Research Center of Health and Environment, Shool of Health, Guilan University of Medical Sciences, Rasht, Iran

R

Richard Welbury

Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK

S

Sasanka S. Chukkapalli

Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA

S

Sim K. Singhrao

Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK

Cite This Article

Bojlul Bahar, Shalini Kanagasingam, Murtaza M. Tambuwala, et al. (2021). Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice. Journal of Alzheimer’s Disease, 82(3), 1259-1275. https://doi.org/10.3233/jad-210465

Porphyromonas gingivalis (W83) Infection Induces Alzheimer’s Disease-Like Pathophysiology in Obese and Diabetic Mice

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