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

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.

Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia

“…In the periphery, infection-induced immune reactions may persist and disarray immunometabolism, resulting in chronic inflammation and increased BBB permeability ( Gustafson et al, 2007 ; Kanoski et al, 2010 ; Montagne et al, 2015 ), which can disrupt the CNS integrity, cognitive ability, and central energy control ( Montagne et al, 2015 ). In addition, infection-induced dysregulation of glucose metabolism can lead to glial activation and neuroinflammation ( Huang et al, 2020 ; Bahar et al, 2021 ). The vicious cycle may further advance the systemic imbalance, while beneficial gut microbiome can restore the balance of immunometabolism.…”

Periodontal microorganisms and Alzheimer disease – A causative relationship?

“…Histologically, chronic P gingivalis or P gingivalis LPS administration increased the number of activated microglial cells and astrocytes in the cortex 148,153 and in the hippocampus 143,145,150,152,154 as an indicator of the local inflammation. Pro‐inflammatory mediators, like IL‐1β, IL‐6, TNFα, INF‐γ, were elevated compared to controls on mRNA and protein level 143,144,146‐150,152‐154 …”

“…140,142,143,146,152 The capability of overcoming the BBB and entering the brain tissue was strain-specific 146 and oral P gingivalis infection was accompanied by protein carbonization in the hippocampal capillaries. 141 Histologically, chronic P gingivalis or P gingivalis LPS administration increased the number of activated microglial cells and astrocytes in the cortex 148,153 and in the hippocampus 143,145,150,152,154 as an indicator of the local inflammation. Proinflammatory mediators, like IL-1β, IL-6, TNFα, INFγ, were elevated compared to controls on mRNA and protein level.…”

“…Of overriding interest were the potential effects in the brain. Porphyromonas gingivalis was identified in the animals' brains after oral administration 140,142,143,146,152 . The capability of overcoming the BBB and entering the brain tissue was strain‐specific 146 and oral P gingivalis infection was accompanied by protein carbonization in the hippocampal capillaries 141 .…”

“…In addition to wild-type or rodent models, type 2 diabetes mellitus mouse models with a gene inactivation for apolipoprotein E (ApoE −/− ) [140][141][142] or leptin receptor (db/db) 143 or transgenic models overexpressing APP 141,144 or even APP and PSEN1 (5XFAD) 145 were infected with P gingivalis or P gingivalis LPS. The infection was administrated by either oral administration, intraperitoneal, or even intracerebroventricular injection.…”