As far back as the eighteenth and early nineteenth centuries, microbial infections were responsible for vast numbers of deaths. The trend reversed with the introduction of antibiotics coinciding with longer life. Increased life expectancy however, accompanied the emergence of age related chronic inflammatory states including the sporadic form of Alzheimer’s disease (AD). Taken together, the true challenge of retaining health into later years of life now appears to lie in delaying and/or preventing the progression of chronic inflammatory diseases, through identifying and influencing modifiable risk factors. Diverse pathogens, including periodontal bacteria have been associated with AD brains. Amyloid-beta (Aβ) hallmark protein of AD may be a consequence of infection, called upon due to its antimicrobial properties. Up to this moment in time, a lack of understanding and knowledge of a microbiome associated with AD brain has ensured that the role pathogens may play in this neurodegenerative disease remains unresolved. The oral microbiome embraces a range of diverse bacterial phylotypes, which especially in vulnerable individuals, will excite and perpetuate a range of inflammatory conditions, to a wide range of extra-oral body tissues and organs specific to their developing pathophysiology, including the brain. This offers the tantalizing opportunity that by controlling the oral-specific microbiome; clinicians may treat or prevent a range of chronic inflammatory diseases orally. Evolution has equipped the human host to combat infection/disease by providing an immune system, but Porphyromonas gingivalis and selective spirochetes, have developed immune avoidance strategies threatening the host-microbe homeostasis. It is clear from longitudinal monitoring of patients that chronic periodontitis contributes to declining cognition. The aim here is to discuss the contribution from opportunistic pathogens of the periodontal microbiome, and highlight the challenges, the host faces, when dealing with unresolvable oral infections that may lead to clinical manifestations that are characteristic for AD.

Background: The effects of the key pathogens and virulence factors associated with gum disease such as Porphyromonas gingivalis (P. gingivalis) on the central nervous system is of great interest with respect to development of neuropathologies and hence therapeutics and preventative strategies. Chronic infections and associated inflammation are known to weaken the first line of defense for the brain, the blood-brain barrier (BBB). Objective: The focus of this study is to utilize an established human in vitro BBB model to evaluate the effects of P. gingivalis virulence factors lipopolysaccharide (LPS) and outer membrane vesicles (OMVs) on a primary-derived human model representing the neurovascular unit of the BBB. Methods: Changes to the integrity of the BBB after application of P. gingivalis LPS and OMVs were investigated and correlated with transport of LPS. Additionally, the effect of P. gingivalis LPS and OMVs on human brain microvascular endothelial cells in monolayer was evaluated using immunofluorescence microscopy. Results: The integrity of the BBB model was weakened by application of P. gingivalis LPS and OMVs, as measured by a decrease in electrical resistance and a recovery deficit was seen in comparison to the controls. Application of P. gingivalis OMVs to a monoculture of human brain microvascular endothelial cells showed disruption of the tight junction zona occludens protein (ZO-1) compared to controls. Conclusion: These findings show that the integrity of tight junctions of the human BBB could be weakened by association with P. gingivalis virulence factors LPS and OMVs containing proteolytic enzymes (gingipains).

The central nervous system (CNS) is protected by a highly selective barrier, the blood-brain barrier (BBB), that regulates the exchange and homeostasis of bloodborne molecules, excluding xenobiotics. This barrier forms the first line of defense by prohibiting pathogens from crossing to the CNS. Aging and chronic exposure of the BBB to pathogens renders it permeable, and this may give rise to pathology in the CNS such as Alzheimer’s disease (AD). Researchers have linked pathogens associated with periodontitis to neuroinflammation and AD-like pathology in vivo and in vitro. Although the presence of periodontitis-associated bacteria has been linked to AD in several clinical studies as DNA and virulence factors were confirmed in brain samples of human AD subjects, the mechanism by which the bacteria traverse to the brain and potentially influences neuropathology is unknown. In this review, we present current knowledge about the association between periodontitis and AD, the mechanism whereby periodontal pathogens might provoke neuroinflammation and how periodontal pathogens could affect the BBB. We suggest future studies, with emphasis on the use of human in vitro models of cells associated with the BBB to unravel the pathway of entry for these bacteria to the CNS and to reveal the molecular and cellular pathways involved in initiating the AD-like pathology. In conclusion, evidence demonstrate that bacteria associated with periodontitis and their virulence factors are capable of inflecting damage to the BBB and have a role in giving rise to pathology similar to that found in AD.

The central nervous system (CNS) is protected by a highly selective barrier, the blood-brain barrier (BBB), that regulates the exchange and homeostasis of bloodborne molecules, excluding xenobiotics. This barrier forms the first line of defense by prohibiting pathogens from crossing to the CNS. Aging and chronic exposure of the BBB to pathogens renders it permeable, and this may give rise to pathology in the CNS such as Alzheimer’s disease (AD). Researchers have linked pathogens associated with periodontitis to neuroinflammation and AD-like pathology in vivo and in vitro. Although the presence of periodontitis-associated bacteria has been linked to AD in several clinical studies as DNA and virulence factors were confirmed in brain samples of human AD subjects, the mechanism by which the bacteria traverse to the brain and potentially influences neuropathology is unknown. In this review, we present current knowledge about the association between periodontitis and AD, the mechanism whereby periodontal pathogens might provoke neuroinflammation and how periodontal pathogens could affect the BBB. We suggest future studies, with emphasis on the use of human in vitro models of cells associated with the BBB to unravel the pathway of entry for these bacteria to the CNS and to reveal the molecular and cellular pathways involved in initiating the AD-like pathology. In conclusion, evidence demonstrates that bacteria associated with periodontitis and their virulence factors are capable of inflecting damage to the BBB and have a role in giving rise to pathology similar to that found in AD.

Background: The effects of the key pathogens and virulence factors associated with gum disease such as Porphyromonas gingivalis (P. gingivalis) on the central nervous system is of great interest with respect to development of neuropathologies and hence therapeutics and preventative strategies. Chronic infections and associated inflammation are known to weaken the first line of defense for the brain, the blood-brain barrier (BBB). Objective: The focus of this study is to utilize an established human in vitro BBB model to evaluate the effects of P. gingivalis virulence factors lipopolysaccharide (LPS) and outer membrane vesicles (OMVs) on a primary-derived human model representing the neurovascular unit of the BBB. Methods: Changes to the integrity of the BBB after application of P. gingivalis LPS and OMVs were investigated and correlated with transport of LPS. Additionally, the effect of P. gingivalis LPS and OMVs on human brain microvascular endothelial cells in monolayer was evaluated using immunofluorescence microscopy. Results: The integrity of the BBB model was weakened by application of P. gingivalis LPS and OMVs, as measured by a decrease in electrical resistance and a recovery deficit was seen in comparison to the controls. Application of P. gingivalis OMVs to a monoculture of human brain microvascular endothelial cells showed disruption of the tight junction zona occludens protein (ZO-1) compared to controls. Conclusion: These findings show that the integrity of tight junctions of the human BBB could be weakened by association with P. gingivalis virulence factors LPS and OMVs containing proteolytic enzymes (gingipains).