Poor Oral Health and its Neurological Consequences: Mechanisms of Porphyromonas gingivalis Involvement in Cognitive Dysfunction

Purpose of review: There is an increasing body of evidence from epidemiology and laboratory investigations on periodontal disease being a risk factor for dementia. In particular, Porphyromonas gingivalis infections in animal models suggest causal associations with Alzheimer’s disease (AD). This review focuses on how P. gingivalis infections promote the incidence of functional loss in AD. Latest findings: The risk of the sporadic form of AD doubles when periodontitis persists for ten or more years. AD differs from other forms of dementia in that the clinical signs together with the presence of amyloid-beta (Aβ) plaques and neurofibrillary tangles must be present at autopsy. P. gingivalis oral infections in mice have demonstrated all of the characteristic pathological and clinical features of AD following infection of the brain. Summary: Multiple factors (inflammation, Aβ oligomers, and bacterial factors) are likely to disrupt neuronal communication channels (synapses) as a plausible explanation for the functional loss

Inflammasome involvement in Alzheimer’s disease

Inflammasomes are responsible for the maturation of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-18 and IL-33 and activation of inflammatory cell death, pyroptosis. They assemble in response to cellular infection and stress or to tissue damage, promote inflammatory reactions and are important in regulating innate immunity particularly by acting as platforms for activation of caspase proteases. They appear to be involved in several pathological processes activated by microbes including Alzheimer’s disease (AD). Best characterized in microbial pathogenesis is the nucleotide-binding domain and leucine-rich repeat (NLR)-protein 3 (NLRP3) inflammasome. AD is a neurodegenerative condition in which the neuropathological hallmarks are the deposition of amyloid beta (Aβ) and hyperphosphorylated tau protein coated neurofibrillary tangles. For decades, the role of the innate immune system in the aetiology of AD was considered less important but the recently discovered inflammatory genes by Genome-wide association studies driving inflammation in this disease has changed this view. Innate immune inflammatory activity in the AD brain can result from the pathological hallmark protein Aβ as well as from specific bacterial infections that tend to possess weak immunostimulatory responses for peripheral blood myeloid cell recruitment to the brain. The weak immunostimulatory activity is a consequence of their immune evasion strategies and survival. In this review we discuss the possibility that inflammasomes, particularly via the NLR family of proteins NLRP3 are involved in the pathogenesis of AD. In addition, we discuss the plausible contribution of specific bacteria playing a role in influencing the activity of the NLRP3 inflammasome to AD progression

Porphyromonas gingivalis infection may contribute to systemic and intracerebral amyloid-beta: Implications for Alzheimer’s disease onset

The microbiota of “chronic” periodontitis, particularly Porphyromonas gingivalis, have been implicated in Alzheimer’s disease (AD) because this bacterium has a range of enzymes (cathepsin B and gingipains) that are shown to interact with the amyloid precursor protein (APP) and neuronal tau resulting in the formation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs). These two lesions remain pivotal to explaining AD pathogenesis alongside of clinical symptoms. Deposits of Aβ in the brain can start 10-20 years before the clinical symptoms of cognitive decline and the diagnosis of AD is established. It is rarely mentioned that the AD risk doubles if the individual has received a diagnosis of periodontitis for around 10 years. This editorial is a review of recent but salient literature supporting the idea that periodontal disease can contribute to a systemic Aβ pool that may enter the brain over time. In addition, intracerebral production of Aβ can be initiated by P. gingivalis, which occurs via host and bacterially derived cathepsin B acting as β-secretase to process the APP via the amyloidogenic pathway yielding Aβ3-42. These findings support a systemic and an intracerebral Aβ contribution from “chronic” periodontitis in subsequent AD development

An evaluation of the molecular mode of action of trans-resveratrol in the Porphyromonas gingivalis lipopolysaccharide challenged neuronal cell model

Abstract I. Background: Porphyromonas gingivalis triggers a range of innate immune responses in the host that can contribute to the development of periodontitis and dementing diseases including Alzheimer's disease (AD). This study aimed to assess the mode of action of trans-resveratrol in modulating the P. gingivalis lipopolysaccharide (PgLPS) induced metabolic inflammation in the neuronal cell model. II. Methods & Results: Confluent IMR-32 neuroblastoma cells were treated with transresveratrol from Polygonum cuspidatum in the presence or absence of PgLPS. The abundance of messenger ribo-nucleic acid (mRNA) transcript of a panel of 92 genes was quantitatively assessed through targeted transcriptome profiling technique and the biochemical pathways affected were identified through Ingenuity Pathway Analysis. Gene expression analysis revealed that trans-resveratrol down-regulated the mRNA of multiple gene markers including growth factors, transcription factors, kinases, trans-membrane receptors, cytokines and enzymes that were otherwise activated by PgLPS treatement of IMR-32 neuroblastoma cells. Pathway analysis demonstrated that the cellular oxidative stress caused by the activation of phosphoinositide-3-kinase/Akt1 (PI3K/Akt1) pathway that leads to the production of reactive oxygen species (ROS), chronic inflammatory response induced by the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway and nutrient utilization pathways were favourably modulated by trans-resveratrol in the PgLPS challenged IMR-32 cells. III. Conclusions: This study demonstrates the potential of trans-resveratrol as a bioactive compound with multiple modes of intracellular action further supporting its therapeutic application in the neuroinflammatory diseases

Porphyromonas gingivalis periodontal infection and its putative links with Alzheimer’s disease

Periodontal disease (PD) and Alzheimer’s disease (AD) are inflammatory conditions affecting the global adult population. In the pathogenesis of PD, subgingival complex bacterial biofilm induces inflammation that leads to connective tissue degradation and alveolar bone resorption around the teeth. In health, junctional epithelium seals the gingiva to the tooth enamel, thus preventing bacteria from entering the gingivae. Chronic PD involves major pathogens (Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia) which have an immune armoury that can circumvent host’s immune surveillance to create, and maintain an inflammatory mediator rich, and toxic environment to grow and survive. The neurodegenerative condition, AD is characterised by poor memory and specific hallmark proteins; periodontal pathogens are increasingly being linked with this dementing condition. It is therefore becoming important to understand associations of periodontitis with relevance to late-onset AD. The aim of this review is to discuss the relevance of finding the keystone periodontal pathogen P. gingivalis in AD brains and its plausible contribution to the aetiological hypothesis of this dementing condition

Periodontitis, pathogenesis and progression: miRNA-mediated cellular responses to Porphyromonas gingivalis

Porphyromonas gingivalis is considered a keystone pathogen in periodontitis, a disease typically driven by dysbiosis of oral inflammophilic polymicrobial pathobionts. To combat infectious agents, the natural defense response of the host is to switch on inflammatory signaling cascades, whereby miRNA species serve as alternative genetic inhibitory transcriptional endpoints. miRNA profiles from diseased sites differ from those detected in disease free tissues. miRNA profiles could therefore be harnessed as potential diagnostic/prognostic tools. The regulatory role of some miRNA species (miRNA-128, miRNA-146, miRNA-203 and miRNA-584) in the innate immune system, suggests these molecular signatures also have potential in therapy. P. gingivalis associated miRNAs are likely to influence the innate immune response whereas its LPS may affect the nature of host miRNAs and their mRNA targets. This mini review discusses miRNA-dependent transcriptional and regulatory phenomena ensuing immune signaling cascade switch-on with development and progression of periodontitis initiated by P. gingivalis lipopolysaccharide (LPS) exposure

Low levels of salivary lactoferrin may affect oral dysbiosis and contribute to Alzheimer’s disease: A hypothesis

Recently it has been reported that reduced levels of salivary lactoferrin (LF) can be a plausible biomarker for amyloid beta (Aβ) accumulation as in the brain of Alzheimer’s disease (AD) brains. This could mean that reduced levels of salivary LF act as a trigger for oral dysbiosis and that low LF levels could change the oral microbiota. A chemical change in the composition of saliva has not yet been considered as a cause for microbial dysbiosis but does present an opportunity to view oral dysbiosis as a plausible contributory factor in the development of AD pathophysiology. Oral dysbiosis has largely been reported as a result of inadequate oral hygiene and dry mouth in elderly subjects. Here we discuss if the deficiency of LF in saliva and gingival fluid of AD patients can facilitate proliferation of oral pathogens, and as a result their spread elsewhere in the body. Additionally, we ask if LF in the AD brain could be overexposed as a result of chronic infection. Together these outcomes will indicate if reduced levels of salivary LF can act as a trigger of oral dysbiosis