Active Invasion of Porphyromonas gingivalis and Infection-Induced Complement Activation in ApoE-/- Mice Brains

Abstract

Periodontal disease is a polymicrobial inflammatory disease that leads to chronic systemic inflammation and direct infiltration of bacteria/bacterial components, which may contribute to the development of Alzheimer's disease. ApoE-/- mice were orally infected (n = 12) with Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum as mono- and polymicrobial infections. ApoE-/- mice were sacrificed following 12 and 24 weeks of chronic infection. Bacterial genomic DNA was isolated from all brain tissues except for the F. nucleatum mono-infected group. Polymerase chain reaction was performed using universal 16 s rDNA primers and species-specific primer sets for each organism to determine whether the infecting pathogens accessed the brain. Sequencing amplification products confirmed the invasion of bacteria into the brain during infection. The innate immune responses were detected using antibodies against complement activation products of C3 convertase stage and the membrane attack complex. Molecular methods demonstrated that 6 out of 12 ApoE-/- mice brains contained P. gingivalis genomic DNA at 12 weeks (p = 0.006), and 9 out of 12 at 24 weeks of infection (p = 0.0001). Microglia in both infected and control groups demonstrated strong intracellular labeling with C3 and C9, due to on-going biosynthesis. The pyramidal neurons of the hippocampus in 4 out of 12 infected mice brains demonstrated characteristic opsonization with C3 activation fragments (p = 0.032). These results show that the oral pathogen P. gingivalis was able to access the ApoE-/- mice brain and thereby contributed to complement activation with bystander neuronal injury.

Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer’s disease

“…All are potential causes for the development of sporadic AD. P. gingivalis was shown to migrate from its oral location to the brain [54,55] where it invoked inflammatory responses typical of neurodegenerative diseases in mice with blood–brain barrier (BBB) damage [55,56]. Ishigami et al [57] identified glial fibrillary acidic protein (GFAP), a marker of astrocytes in the AD brain, to be a substrate for host PAD2, and suggested a role for the citrullinated GFAP in the progression of this neurodegenerative disease.…”

Cerebral Oxidative Stress and Microvasculature Defects in TNF-α Expressing Transgenic and Porphyromonas gingivalis-Infected ApoE–/– Mice

“…Once in the brain, P. gingivalis modulates innate immune responses via activation of the complement cascade, resulting in bystander injury of functional pyramidal neurons in the hippocampus, following 24 week of chronic infection [34]. A recent investigation using the same ApoE -/-P.…”

“…We have previously reported associations between P. gingivalis LPS and AD brains [33] and subsequently established that P. gingivalis is capable of accessing ApoE -/-mouse brains from its primary gingival location [32,34]. Once in the brain, P. gingivalis modulates innate immune responses via activation of the complement cascade, resulting in bystander injury of functional pyramidal neurons in the hippocampus, following 24 week of chronic infection [34].…”

Apolipoprotein E Related Co-Morbidities and Alzheimer’s Disease

“…The downstream effects of P. gingivalis mono-infection in ApoE -/-mice was recently reported by Poole et al [132] in which they reported the translocation of this PD pathogen from the oral cavity into the brain tissue likely via the haematogenous route; although other pathways for its translocation are also possible [133].…”

“…Examination of the brain tissue highlighted the brains own inflammatory cells (microglia and astrocytes) were activated and neurons were being attacked by excessive complement activation supporting ongoing intracerebral inflammation in the absence of AD hallmark proteins [132]. For the relevance of finding P.…”