Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review

Frontiers in Aging Neuroscience, Journal Year: 2018, Volume and Issue: 10

Published: Feb. 22, 2018

This review proposes that LPS (Lipopolysaccharide, found in the wall of all Gram-negative bacteria) could play a role causing sporadic Alzheimer's Disease (AD). is based part upon recent studies showing that: E coli bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA present human brains with over 70% being bacteria; ultrastructural analyses have shown microbes erythrocytes AD patients; blood levels patients are 3-fold control; combined focal cerebral ischemia and hypoxia produced amyloid-like plaques myelin injury adult rat cortex. Moreover, bacterial was aging control brains, though were much higher brains. In addition, co-localized amyloid plaques, peri-vascular amyloid, neurons, oligodendrocytes Based postulate caused oligodendrocyte injury, degraded Myelin Basic Protein (dMBP) to be compared Immunofluorescence showed dMBP β (Aβ) brain, other molecules walls vesicles periventricular white matter. These data led hypothesis acts on leukocyte microglial TLR4-CD14/TLR2 receptors produce NFĸB mediated increases cytokines which increase Aβ levels, damage brain. Since Aβ1-42 also an agonist for TLR4 receptors, this vicious cycle accounts relentless progression AD. Thus, LPS, receptor complex, might treatment or prevention targets Keywords: disease, Lipopolysaccharide, Cytokines, TLR4, CD14, Myelin, MBP, oligodendrocytes, Amyloid plaque, perivascular

Language: Английский

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Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice

PLoS ONE, Journal Year: 2018, Volume and Issue: 13(10), P. e0204941 - e0204941

Published: Oct. 3, 2018

Background The results from cross sectional and longitudinal studies show that periodontitis is closely associated with cognitive impairment (CI) Alzhemer's Disease (AD). Further, using animal model of human post-mortem brain tissues subjects AD strongly suggest a gram-negative periodontal pathogen, Porphyromonas gingivalis (Pg) and/or its product gingipain is/are translocated to the brain. However, neuropathology resulting Pg oral application not known. In this work, we tested hypothesis repeated exposure wild type C57BL/6 mice orally administered in neuroinflammation, neurodegeneration, microgliosis, astrogliosis formation intra- extracellular amyloid plaque neurofibrillary tangles (NFTs) which are pathognomonic signs AD. Methods Experimental chronic was induced ten 8-week old WT by (MWF/week) Pg/gingipain for 22 weeks (experimental group). Another 10 received vehicle alone (control group) MWF per week weeks. Brain were collected presence determined immunofluorescence (IF) microscopy, confocal quantitative PCR (qPCR). hippocampi examined related AD: TNFα, IL1β, IL6 expression (neuroinflammation), NeuN Fluoro Jade C staining (neurodegeneration) beta1-42 (Aβ42) production phosphorylation tau protein at Ser396 assessed IF microscopy. gene precursor (APP), beta-site APP cleaving enzyme 1 (BACE1), disintegrin metalloproteinase domain-containing protein10 (ADAM10) α-secretase presenilin1 (PSEN1) ɣ-secretase, (rbFox3) RT-qPCR. Microgliosis also Results detected experimental group immunohistochemistry, qPCR confirming translocation applied localized intra-nuclearly peri-nuclearly microglia (Iba1+), astrocytes (GFAP+), neurons (NeuN+) evident extracellularly. Significantly greater levels IL6, TNFα IL1β as compared control (p<0.01, p<0.00001, p<0.00001 respectively). addition, microgliosis but (p <0.01, p<0.0001 Neurodegeneration based on fewer number intact neuronal cells positivity rbFOX3 expression, there degenerating positivity. BACE1 increased (p<0.05, p<0.001 PSEN1 higher than difference statistically significant = 0.07). ADAM10 significantly decreased (p<0.01). Extracellular Aβ42 parenchyma (p< 0.00001). Finally, phospho-Tau (Ser396) NFTs (p<0.00001). Conclusions This study first neurodegeneration young adult after Pg. neuropathological features observed low grade pathogen infection can result development consistent

Language: Английский

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TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: April 23, 2020

Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), abnormal aggregates hyperphosphorylated tau protein neurons, are two pathological hallmarks Alzheimer’s disease (AD). Fibrillar Aβ deposits accompanied with neuroinflammation synapse loss, characterized by activated microglia dystrophic neurites. Genome-wide association studies on patients late-onset AD have identified a dozen genetic risk variants that involved innate immune responses, highlighting importance cells pathogenesis AD. Additional lines evidence support notion microglia, central nervous system (CNS), play pivotal, dual roles progression: either clearing phagocytosis promoting neuron survival plasticity or releasing cytotoxic chemicals, inflammatory cytokines, exacerbating load synaptotoxicity. Aggregated binds to toll-like receptor 4 (TLR4) activates resulting increased cytokine production. Complement components associated plaques NFTs. can activate complement, leading pruning loss microglial phagocytosis. Systemic inflammation TLR4, NLRP3 inflammasome, complement brain, neuroinflammation, accumulation, neurodegeneration. The host response has been shown function through complex crosstalk between TLR, inflammasome signaling pathways. Accordingly, targeting molecular mechanisms underlying TLR-complement-NLRP3 pathways be preventive therapeutic approach for

Language: Английский

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The impact of the microbiota-gut-brain axis on Alzheimer’s disease pathophysiology

Pharmacological Research, Journal Year: 2020, Volume and Issue: 164, P. 105314 - 105314

Published: Nov. 25, 2020

Language: Английский

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Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer’s Disease?

Frontiers in Aging Neuroscience, Journal Year: 2018, Volume and Issue: 10

Published: July 24, 2018

Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks are extracellular senile plaques composed beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles pTau. These findings led to "beta-amyloid hypothesis" that proposes Aβ major cause AD. Clinical trials targeting in brain have mostly failed, whether they attempted decrease production by BACE inhibitors or antibodies. failures suggest a need find new hypotheses explain AD pathogenesis generate targets for intervention prevent treat disease. Many years ago, "infection was proposed, but received little attention. However, recent discovery an antimicrobial (AMP) acting against bacteria, fungi, viruses gives increased credence infection hypothesis etiology We others shown microbial increases synthesis this AMP. Here, we propose as AMP will be beneficial on first challenge become progressively detrimental becomes chronic reactivates from time time. Furthermore, host measures remove excess over due microglial senescence biofilm formation. aggregates with form patients. In review, develop connection between Infection - discuss future possible treatments based paradigm.

Language: Английский

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The Role of Periodontitis and Periodontal Bacteria in the Onset and Progression of Alzheimer’s Disease: A Systematic Review

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 9(2), P. 495 - 495

Published: Feb. 11, 2020

The evidence of a connection between the peripheral inflammatory processes and neurodegenerative diseases central nervous system is becoming more apparent. This review related literature highlights most recent clinical, epidemiological, in vitro studies trying to investigate possible connections periodontal bacteria onset progression Alzheimer's disease. was conducted by searching databases such as PubMed Scopus using keywords or combinations Disease AND dementia periodontitis OR periodontal. After eliminating overlaps screening articles not these issues, we identified 1088 records proceeded selection for an evaluation associative assumptions. hypothesis suggested authors confirmed that bacterial load process linked disease can intensify inflammation at level system, favoring occurrence analysis how directly contribute environment introduction indirect pathogenic proinflammatory cytokines locally produced following colonization defects.

Language: Английский

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Periodontal microorganisms and Alzheimer disease – A causative relationship?

Periodontology 2000, Journal Year: 2022, Volume and Issue: 89(1), P. 59 - 82

Published: March 4, 2022

Abstract In the initiation or exacerbation of Alzheimer disease, dissemination oral microorganisms into brain tissue low‐level systemic inflammation have been speculated to play a role. However, impact microorganisms, such as Porphyromonas gingivalis , on pathogenesis disease and potential causative relationship is still unclear. The present review has critically reviewed literature by examining following aspects: (a) microbiome immune response in elderly population, (b) human studies association between periodontal gut (c) animal vitro (d) preventive therapeutic approaches. Factors contributing microbial dysbiosis seem be aging, local inflammation, diseases, wearing dentures, living nursing homes no access adequate hygiene measures. was detectable post‐mortem samples. Microbiome analyses saliva samples biofilms showed decreased diversity different composition compared cognitively healthy subjects. Many in‐vitro underline P induce disease‐related alterations. models, recurring applications its components increased pro‐inflammatory mediators β‐amyloid deteriorated animals' cognitive performance. Since periodontitis result disturbed homoeostasis, an effect therapy host related parameters may suggested should elucidated further clinical trials.

Language: Английский

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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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Time to test antibacterial therapy in Alzheimer’s disease

Brain, Journal Year: 2019, Volume and Issue: unknown

Published: July 25, 2019

Alzheimer's disease is associated with cerebral accumulation of amyloid-β peptide and hyperphosphorylated tau. In the past 28 years, huge efforts have been made in attempting to treat by reducing brain patients disease, no success. While anti-amyloid-β therapies continue be tested prodromal subjects at risk developing there an urgent need provide therapeutic support established for whom current symptomatic treatment (acetylcholinesterase inhibitors N-methyl d-aspartate antagonist) limited help. The possibility infectious aetiology has repeatedly postulated over three decades. Infiltration pathogens may act as a trigger or co-factor Herpes simplex virus type 1, Chlamydia pneumoniae, Porphyromonas gingivalis being most frequently implicated. These directly cross weakened blood-brain barrier, reach CNS cause neurological damage eliciting neuroinflammation. Alternatively, intestinal vascular circulation then barrier low grade chronic inflammation subsequent neuroinflammation from periphery. gut microbiota comprises complex community microorganisms. Increased permeability induced dysbiosis impact pathogenesis. Inflammatory microorganisms are peripheral deposition cognitive impairment. Oral also influence through circulatory neural access brain. At least two possibilities can envisaged explain association suspected disease. One that particularly prone microbial infections. other infection contributing Therapeutic trials antivirals and/or antibacterials could resolve this dilemma. Indeed, antiviral agents double-blind placebo-controlled studies. Although combined antibiotic therapy was found effective animal models antibacterial drugs not widely investigated This because it clear which bacterial populations overexpressed if safe, selective available them. On hand, protease inhibitor targeting P. toxins now Clinical studies needed test countering beneficial

Language: Английский

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Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Journal Year: 2020, Volume and Issue: 1868(8), P. 140428 - 140428

Published: April 17, 2020

Language: Английский

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