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

Article type: Research Article

Authors: Bahar, Bojlul^a | Kanagasingam, Shalini^b | Tambuwala, Murtaza M.^c | Aljabali, Alaa A.A.^d | Dillon, Stephanie A.^a | Doaei, Saeid^e | Welbury, Richard^b | Chukkapalli, Sasanka S.^f | Singhrao, Sim K.^{b; *}

Affiliations: [a] Nutrition Sciences and Applied Food Safety Studies, Research Centre for Global Development, School of Sport & Health Sciences, University of Central Lancashire, Preston, UK | [b] Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK | [c] School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine, County Londonderry, Northern Ireland, UK | [d] Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, Irbid, Jordan | [e] Research Center of Health and Environment, Shool of Health, Guilan University of Medical Sciences, Rasht, Iran | [f] Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA

Correspondence: [*] Correspondence to: Sim K. Singhrao, Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, PR1 2HE, UK. Tel.: +44 0 1772 895137; E-mail: SKSinghrao@uclan.ac.uk.

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.

Keywords: Alzheimer’s disease, diabetes genes, insulin resistance, Porphyromonas gingivalis

DOI: 10.3233/JAD-210465

Journal: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1259-1275, 2021