Outer membrane vesicles of Porphyromonas gingivalis trigger NLRP3 inflammasome and induce neuroinflammation, tau phosphorylation, and memory dysfunction in mice

Frontiers in Cellular and Infection Microbiology, Journal Year: 2022, Volume and Issue: 12

Published: Aug. 9, 2022

Background Porphyromonas gingivalis (Pg), the keystone pathogen in chronic periodontitis, is reported to initiate Alzheimer’s disease pathologies preclinical studies. However, specific mechanisms and signaling pathways acting on brain still need be further explored. Outer membrane vesicles are derived from Gram-negative bacteria contain many virulence factors of bacteria. We hypothesized that outer an important weapon pathologies. Methods The (Pg OMVs, 4 mg/kg) or saline were delivered 14-month-old mice by oral gavage every other day for eight weeks. Behavioral alterations assessed open field test, Morris water maze, Y-maze test. Blood–brain barrier permeability, neuroinflammation, tau phosphorylation, NLRP3 inflammasome-related protein analyzed. Results Pg OMVs impaired memory learning ability decreased tight junction–related gene expression ZO-1, occludin, claudin-5, occludin hippocampus. could detected hippocampus cortex three days after gavage. Furthermore, activated both astrocytes microglia elevated IL-1β, phosphorylation Thr231 site, inflammasome–related In vitro studies, OMV (5 µg/ml) stimulation increased mRNA immunofluorescence BV2 microglia, which significantly inhibited inhibitor MCC950. contrast, N2a neurons was enhanced treatment with conditioned media OMV-stimulated attenuated pretreatment Conclusions These results indicate prompt dysfunction, trigger inflammasome middle-aged mice. propose play role activating neuroinflammation AD-like pathology triggered , activation a possible mechanism.

Language: Английский

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

Neurochemistry International, Journal Year: 2022, Volume and Issue: 154, P. 105282 - 105282

Published: Jan. 13, 2022

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

Language: Английский

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Zinc in Cognitive Impairment and Aging

Biomolecules, Journal Year: 2022, Volume and Issue: 12(7), P. 1000 - 1000

Published: July 18, 2022

Zinc, an essential micronutrient for life, was first discovered in 1869 and later found to be indispensable the normal development of plants growth rats birds. Zinc plays important role many physiological pathological processes mammalian brain development, especially central nervous system. deficiency can lead neurodegenerative diseases, mental abnormalities, sleep disorders, tumors, vascular other conditions, which cause cognitive impairment premature aging. This study aimed review effects zinc zinc-associated proteins aging, reveal its molecular mechanism, highlight potential interventions aging impairments.

Language: Английский

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The role of microbiome-host interactions in the development of Alzheimer´s disease

Frontiers in Cellular and Infection Microbiology, Journal Year: 2023, Volume and Issue: 13

Published: June 2, 2023

Alzheimer`s disease (AD) is the most prevalent cause of dementia. It often assumed that AD caused by an aggregation extracellular beta-amyloid and intracellular tau-protein, supported a recent study showing reduced brain amyloid levels cognitive decline under treatment with beta-amyloid-binding antibody. Confirmation importance as therapeutic target notwithstanding, underlying causes in human brain, however, remain to be elucidated. Multiple lines evidence point towards important role infectious agents and/or inflammatory conditions etiology AD. Various microorganisms have been detected cerebrospinal fluid brains AD-patients thus hypothesized linked development AD, including Porphyromonas gingivalis (PG) Spirochaetes . Intriguingly, these are also found oral cavity normal physiological conditions, which affected multiple pathologies like caries or tooth loss patients. Oral mostly accompanied compositional shift community microbiota, mainly affecting commensal referred ‘dysbiosis’. dysbiosis seems at least partly mediated key pathogens such PG, it associated pro-inflammatory state promotes destruction connective tissue mouth, possibly enabling translocation pathogenic microbiota from nervous system. has therefore microbiome may contribute In this review, we discuss hypothesis light microbiome-host interactions, even We technical challenges relating detection relevant body fluids approaches for avoiding false-positives, introduce antibacterial protein lactoferrin potential link between dysbiotic host reaction.

Language: Английский

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Alzheimer’s Disease and Porphyromonas gingivalis: Exploring the Links

Life, Journal Year: 2025, Volume and Issue: 15(1), P. 96 - 96

Published: Jan. 14, 2025

Recent research highlights compelling links between oral health, particularly periodontitis, and systemic diseases, including Alzheimer's disease (AD). Although the biological mechanisms underlying these associations remain unclear, role of periodontal pathogens, Porphyromonas gingivalis, has garnered significant attention. P. a major driver is recognized for its potential effects putative in AD pathogenesis. This review examines evidence connecting gingivalis to hallmark features, such as amyloid β accumulation, tau hyperphosphorylation, neuroinflammation, other neuropathological features consistent with AD. Virulence factors, gingipains lipopolysaccharides, were shown be implicated blood-brain barrier disruption, neuronal damage. gingivalis-derived outer membrane vesicles may serve disseminate virulence factors brain tissues. Indirect mechanisms, inflammation triggered by chronic infections, are also supposed exacerbate neurodegenerative processes. While exact pathways uncertain, studies detecting components AD-affected brains support their possible underscores need further investigation into gingivalis-mediated interplay host responses. Understanding interactions could provide critical insights novel strategies reducing risk through management.

Language: Английский

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Oral bacteriophages and their potential as adjunctive treatments for periodontitis: a narrative review

Journal of Oral Microbiology, Journal Year: 2025, Volume and Issue: 17(1)

Published: Feb. 25, 2025

Background There is no specific cure for periodontitis and treatment symptomatic, primarily by physical removal of the subgingival plaque biofilm. Current non-surgical periodontal therapy becomes less effective as pocket depth increases such new adjunctive treatments are required. The development antibiotic resistance has driven a recent resurgence interest in bacteriophage therapy.

Language: Английский

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Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders

Frontiers in Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Feb. 25, 2022

The human gut microbiota is a complex, dynamic, and highly diverse community of microorganisms. Beginning as early in utero fetal development continuing through birth to late-stage adulthood, the crosstalk between microbiome brain essential for modulating various metabolic, neurodevelopmental, immune-related pathways. Conversely, microbial dysbiosis – defined alterations richness relative abundances implicated pathogenesis several chronic neurological neurodegenerative disorders. Evidence from large-population cohort studies suggests that individuals with conditions have an altered composition well serum metabolomic profiles distinct those healthy population. Dysbiosis also linked psychiatric gastrointestinal complications comorbidities often associated prodromal phase Parkinson’s disease (PD) Alzheimer’s (AD). Studies identified potential mediators link Recent findings elucidated mechanisms pathology enteric nervous system prior onset neurodegeneration. This review highlights functional pathways mechanisms, particularly microbe-induced inflammation, protein misfolding, propagation disease-specific pathology, defective clearance, autoimmune dysregulation, linking In addition, we discuss how pathogenic transformation leads increased endotoxin production fewer beneficial metabolites, both which could trigger immune cell activation neuronal dysfunction. These can further disrupt intestinal barrier permeability, aggravate systemic pro-inflammatory state, impair blood–brain permeability recruit leading neuroinflammation Continued biomedical advances understanding microbiota-gut-brain axis will extend frontier disorders enable utilization novel diagnostic therapeutic strategies mitigate pathological burden these diseases.

Language: Английский

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Biomarker and therapeutic potential of peripheral extracellular vesicles in Alzheimer’s disease

Advanced Drug Delivery Reviews, Journal Year: 2022, Volume and Issue: 190, P. 114486 - 114486

Published: Aug. 9, 2022

Language: Английский

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An Investigation into the Effects of Outer Membrane Vesicles and Lipopolysaccharide of Porphyromonas gingivalis on Blood-Brain Barrier Integrity, Permeability, and Disruption of Scaffolding Proteins in a Human in vitro Model

Journal of Alzheimer s Disease, Journal Year: 2022, Volume and Issue: 86(1), P. 343 - 364

Published: Jan. 11, 2022

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

Language: Английский

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Engineered bacterial extracellular vesicles for central nervous system diseases

Journal of Controlled Release, Journal Year: 2023, Volume and Issue: 364, P. 46 - 60

Published: Oct. 25, 2023

Language: Английский

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