Cerebral Oxidative Stress and Microvasculature Defects in TNF-α Expressing Transgenic and Porphyromonas gingivalis-Infected ApoE–/– Mice

Rokad, Farheen; Moseley, Ryan; Hardy, Rowan; Chukkapalli, Sasanka S.; Crean, St John; Kesavalu, Lakshmyya; Singhrao, Simarjit Kaur

doi:10.3233/jad-170304

Cited by 32 publications

(35 citation statements)

References 56 publications

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“…In order to investigate the contribution of peripheral inflammatory responses on oxidative stress in the brain, Rokad et al infected TNF-α transgenic mice with P. gingivalis . These mice express a stabilized version of TNF-α mRNA, resulting in overexpression of TNF-α protein in most tissues, including the brain (Rokad et al, 2017). In these mice, P. gingivalis infection increased the proportion of oxidized proteins in whole brain lysates, suggesting that P. gingivalis may contribute to cellular damage and downstream protein oxidation.…”

Section: Bacterial Pathogens Associated With Neurodegenerationmentioning

confidence: 99%

Exploring the “Multiple-Hit Hypothesis” of Neurodegenerative Disease: Bacterial Infection Comes Up to Bat

Patrick

Bell

Weindel

et al. 2019

Front. Cell. Infect. Microbiol.

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Despite major strides in personalized genomics, it remains poorly understood why neurodegenerative diseases occur in only a fraction of individuals with a genetic predisposition and conversely, why individuals with no genetic risk of a disorder develop one. Chronic diseases like Alzheimer's, Parkinson's, and Multiple sclerosis are speculated to result from a combination of genetic and environmental factors, a concept commonly referred to as the “multiple hit hypothesis.” A number of bacterial infections have been linked to increased risk of neurodegeneration, and in some cases, clearance of bacterial pathogens has been correlated with amelioration of central nervous system (CNS) deficits. Additionally, mutations in several genes known to contribute to CNS disorders like Parkinson's Disease have repeatedly been implicated in susceptibility to intracellular bacterial infection. Recent data has begun to demonstrate roles for these genes ( PARK2, PINK1 , and LRRK2 ) in modulating innate immune outcomes, suggesting that immune dysregulation may play an even more important role in neurodegeneration than previously appreciated. This review will broadly explore the connections between bacterial infection, immune dysregulation, and CNS disorders. Understanding this interplay and how bacterial pathogenesis contributes to the “multiple-hit hypothesis” of neurodegeneration will be crucial to develop therapeutics to effectively treat both neurodegeneration and infection.

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Section: Bacterial Pathogens Associated With Neurodegenerationmentioning

confidence: 99%

Exploring the “Multiple-Hit Hypothesis” of Neurodegenerative Disease: Bacterial Infection Comes Up to Bat

Patrick

Bell

Weindel

et al. 2019

Front. Cell. Infect. Microbiol.

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“…In support of this hypothesis, P. gingivalis infected animal models demonstrated hippocampal damage via inflammation-mediated injury and IgG and gingipains in the cerebral microvasculature (Singhrao et al, 2017 ). In addition, the phagocytic oxidative burst of the host’s neutrophils and macrophages at a much earlier time point of P. gingivalis infection, and the oxidative stress response initiated by bacteria can equally damage the hippocampal microvasculature (Rokad et al, 2017 ). A permeable BBB also has implications for entry of extra-cerebral amyloid/amyloid-like proteins to the brain and add to the existing amyloid burden.…”

Section: Senile Plaque a Miniature Biofilm Hypothesismentioning

confidence: 99%

Periodontitis, Microbiomes and their Role in Alzheimer’s Disease

Pritchard

Crean

Olsen

et al. 2017

Front. Aging Neurosci.

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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.

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“…All are potential causes for the development of sporadic AD. P. gingivalis was shown to migrate from its oral location to the brain [54,55] where it invoked inflammatory responses typical of neurodegenerative diseases in mice with blood–brain barrier (BBB) damage [55,56]. Ishigami et al [57] identified glial fibrillary acidic protein (GFAP), a marker of astrocytes in the AD brain, to be a substrate for host PAD2, and suggested a role for the citrullinated GFAP in the progression of this neurodegenerative disease.…”

Section: Introductionmentioning

confidence: 99%

Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer’s disease

Olsen

Singhrao

Potempa

2018

Journal of Oral Microbiology

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Periodontitis, rheumatoid arthritis (RA), atherosclerosis (AS), and Alzheimer’s disease (AD) are examples of complex human diseases with chronic inflammatory components in their etiologies. The initial trigger of inflammation that progresses to these diseases remains unresolved. Porphyromonas gingivalis is unique in its ability to secrete the P. gingivalis-derived peptidyl arginine deiminase (PPAD) and consequently offers a plausible and exclusive link to these diseases through enzymatic conversion of arginine to citrulline. Citrullination is a post-translational enzymatic modification of arginine residues in proteins formed as part of normal physiological processes. However, PPAD has the potential to modify self (bacterial) and host proteins by deimination of arginine amino acid residues, preferentially at the C-terminus. Migration of P. gingivalis and/or its secreted PPAD into the bloodstream opens up the possibility that this enzyme will citrullinate proteins at disparate body sites. Citrullination is associated with the pathogenesis of multifactorial diseases such as RA and AD, which have an elusive external perpetrator as they show epidemiological associations with periodontitis. Therefore, PPAD deserves some prominence as an external antigen, in at least, a subset of RA and AD cases, with as yet unidentified, immune/genetic vulnerabilities.

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Cerebral Oxidative Stress and Microvasculature Defects in TNF-α Expressing Transgenic and Porphyromonas gingivalis-Infected ApoE–/– Mice

Cited by 32 publications

References 56 publications

Exploring the “Multiple-Hit Hypothesis” of Neurodegenerative Disease: Bacterial Infection Comes Up to Bat

Exploring the “Multiple-Hit Hypothesis” of Neurodegenerative Disease: Bacterial Infection Comes Up to Bat

Periodontitis, Microbiomes and their Role in Alzheimer’s Disease

Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer’s disease

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