Interaction between genetic factors, <i>Porphyromonas gingivalis</i> and microglia to promote Alzheimer’s disease

Olsen, Ingar; Singhrao, Simarjit Kaur

doi:10.1080/20002297.2020.1820834

Cited by 25 publications

(23 citation statements)

References 86 publications

(146 reference statements)

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“…Periodontitis can exert its influence indirectly by sustaining peripheral inflammation. This together with defective susceptibility genes that normally help with clearance of waste from the brain, can prime microglial cells into a pro-inflammatory phenotype [ 20 ].…”

Section: What Makes P Gingivalis a Risk Factor Fomentioning

confidence: 99%

Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer’s Disease

Kanagasingam

Chukkapalli

Welbury

et al. 2020

Journal of Alzheimer's Disease Reports

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Porphyromonas gingivalis (P. gingivalis) is one of the several important bacterial pathogens associated with the sporadic Alzheimer’s disease (AD). Different serotypes are either capsulated or are non-capsulated. It has been demonstrated that P. gingivalis (non-capsulated) can reproduce the neurodegenerative AD-like changes in vitro, and a capsular P. gingivalis (strain W83) could reproduce the cardinal hallmark lesions of AD in a wild-type mouse model. All P. gingivalis forms express proteolytically active proteases that enable cleavage of the amyloid-β protin precursor (AβPP) and tau resulting in the formation of amyloid-β and neurofibrillary tangles. Tau is an established substrate for gingipains, which can cleave tau into various peptides. Some of the P. gingivalis fragmented tau protein peptides contain “VQIINK” and “VQIVYK” hexapeptide motifs which map to the flanking regions of the microtubule binding domains and are also found in paired helical filaments that form NFTs. P. gingivalis can induce peripheral inflammation in periodontitis and can also initiate signaling pathways that activate kinases, which in turn, phosphorylate neuronal tau. Periodontal disease related inflammation has metabolic implications for an individual’s peripheral and brain health as patients suffering from generalized periodontitis often have related co-morbidities and are “at risk” of developing AD. The aim here is to discuss the role of P. gingivalis behind such associations with the backdrop of huge efforts to test P. gingivalis virulence factors clinically (GAIN Trial: Phase 2/3 Study of COR388 in Subjects with AD) with inhibitors, which may lead to an intervention by reducing the pathogenic bacterial load.

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Section: What Makes P Gingivalis a Risk Factor Fomentioning

confidence: 99%

Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer’s Disease

Kanagasingam

Chukkapalli

Welbury

et al. 2020

Journal of Alzheimer's Disease Reports

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“…The interaction between genetic factors, microglia, and P. gingivalis was reviewed by Olsen and Singhrao (2020) . It was suggested that genes for apolipoprotein, clusterin, CD33, triggering receptor expressed on myeloid cells-2, tyrosine kinase binding protein (TYR-OBP), and complement receptors could affect microglia.…”

Section: Microglia and Porphyromonas Gingivalismentioning

confidence: 99%

Porphyromonas gingivalis-Induced Neuroinflammation in Alzheimer’s Disease

Olsen

2021

Front. Neurosci.

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“Chronic” periodontitis and its keystone pathogen Porphyromonas gingivalis have repeatedly been associated with Alzheimer’s disease (AD). Pathological hallmarks in AD are brain accumulations of amyloid-beta and neurofibrillary tangles consisting of aggregated and hyperphosphorylated tau. In addition, neuroinflammation induced by P. gingivalis has increasingly been recognized as a factor in the pathogenesis of AD. The present mini-review discusses possible mechanisms for the induction of neuroinflammation by P. gingivalis in AD, involving factors such as pro-inflammatory mediators, amyloid-beta, tau, microglia, cathepsin B, and protein kinase R. Inflammagens of P. gingivalis such as lipopolysaccharide and gingipains are also discussed.

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“…Depending on the trigger of activation, M1 can exert cytotoxic (pro-inflammatory cytokine release) and M2 neuroprotective (immune resolution) effects [52]. The chronic nature of low-level infections such as gingivitis/periodontitis and associated by products, e.g., endo/exotoxins and cytokines could affect the capacity of susceptible brains' defense to a point where microglia, "remembering" previous P. gingivalis exposure, turn into the M1 phase [50,53].…”

Section: Amyloid-␤ Occurs In the Brain Of Both Healthy And Ad Peoplementioning

confidence: 99%

“…It is also possible that Aβ in healthy older people gradually contributes to neuroinflammation and neurodegeneration when microglia activation develops as a protective response to P. gingivalis [ 50 ]. Microglia have a dual role in the pathogenesis of AD.…”

Section: Amyloid-β Occurs In the Brain Of Both Healthy And Ad Peoplementioning

confidence: 99%

Can Porphyromonas gingivalis Contribute to Alzheimer’s Disease Already at the Stage of Gingivitis?

Olsen

2021

ADR

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Alzheimer’s disease (AD) has been associated with periodontitis, which starts as gingivitis. Similar to periodontitis, gingivitis bacteria, bacterial products, and inflammatory mediators can travel to the brain via the blood stream and promote brain inflammation. Periodontal pathogens such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, both associated with AD, have been found in dental plaque of children already at the age of 3. It is suggested that these bacteria during long-term exposure may drive microglia (brain resident macrophage cells) into a pro-inflammatory M1 phase where they contribute to AD rather than protect against it. This notion comes from studies in mice showing that microglia actually can “remember” previous inflammatory challenge and become “trained” or “tolerant” to toxins like lipopolysaccharide. If gingivitis has an impact on AD, which should be verified, AD prophylaxis should start already at this pre-periodontitis stage with removal of supragingival plaque.

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Interaction between genetic factors, Porphyromonas gingivalis and microglia to promote Alzheimer’s disease

Cited by 25 publications

References 86 publications

Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer’s Disease

Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer’s Disease

Porphyromonas gingivalis-Induced Neuroinflammation in Alzheimer’s Disease

Can Porphyromonas gingivalis Contribute to Alzheimer’s Disease Already at the Stage of Gingivitis?

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