Oftentimes patients may wonder what the worst-case scenario of neglecting their oral health leads to? Root canals may come to mind, but few are aware of the recent findings that indicate gum disease, or gingivitis, can even lead to Alzheimer's. Though the connection may be shocking to some, it makes sense when considering the importance of our oral microbiome and how complete, whole-body health starts in the mouth.

The gut-brain axis needs to include the mouth in this discussion as this is where it all truly begins. Key-playing bacteria found in periodontal disease and gingivitis have been discovered in the brains of Alzheimer’s disease patients. They found DNA 🧬 of this bacteria in postmortem brains and living individuals' cerebral spinal fluid. Then they orally infected mice with P. gingivalis and witnessed brain colonization along with increased amyloid plaque production. They concluded that amyloid plaques may be an antimicrobial response to the Lipopolysacharride and gingipains of this bacteria. Recently the mechanism underlying how this occurs was discovered. Gingipains are toxic proteases that can break down tight junction proteins. When these bacteria get into the bloodstream they can break down the tight junctions of the endothelial lining of the blood-brain barrier.

Supporting Studies:

PMC6357742 - Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitor

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357742/

Abstract: "Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer’s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer’s patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aβ1–42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1–42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer’s disease."

PMID: 35032577 - Secreted gingipains from Porphyromonas gingivalis increase permeability in human cerebral microvascular endothelial cells through intracellular degradation of tight junction proteins

https://pubmed.ncbi.nlm.nih.gov/35032577/

Abstract: Despite a clear correlation between the infiltration of periodontal pathogens in the brain and cognitive decline in Alzheimer's disease (AD), the precise mechanism underlying bacteria crossing the blood-brain barrier (BBB) remains unclear. The periodontal pathogen Porphyromonas gingivalis produces a unique class of cysteine proteases termed gingipains. Gingipains appear to be key virulence factors that exacerbate sporadic AD. We herein report that gingipains are involved in increasing permeability of hCMEC/D3 cell monolayer, human cerebral microvascular endothelial cell lines, through degradation of tight junction proteins including Zonula occludens-1 (ZO-1) and occludin. There was a significant decrease in the mean protein levels of ZO-1 and occludin after infection of hCMEC/D3 cells with wild-type (WT) P. gingivalis. However, infection of these cells with a gingipain-deficient P. gingivalis strain showed significantly lower reduction of the mean protein levels of either ZO-1 and occludin, compared to the WT strain. Similar results were obtained after treatment with culture supernatant from WT and gingipain-deficient P. gingivalis strains. In vitro digestion of human recombinant ZO-1 and occludin by WT P. gingivalis culture supernatant in the absence or presence of gingipain inhibitors indicated that gingipains directly degraded these tight junction proteins. A close immunohistochemical examination using anti-gingipain antibody further revealed that gingipains localized in the cytosol and nuclei of hCMEC/D3 cells after infection with WT P. gingivalis and treatment with its culture supernatant. Furthermore, intracellular localization of outer membrane vesicles (OMVs) bound gingipains from WT P. gingivalis and OMV-induced degradation of ZO-1 and occludin were also observed in hCMEC/D3 cells. Thus, the delivery of gingipains into the cerebral microvascular endothelial cells, probably through OMV, may be responsible for the BBB damage through intracellular degradation of ZO-1 and occludin."