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Porphyromonas Gingivalis Is a Strong Risk Factor for Alzheimer's Disease

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Porphyromonas Gingivalis Is a Strong Risk Factor for Alzheimer's Disease Journal of Alzheimer’s Disease Reports 4 (2020) 501–511 501 DOI 10.3233/ADR-200250 IOS Press Review Porphyromonas gingivalis is a Strong Risk Factor for Alzheimer’s Disease Shalini Kanagasingama, Sasanka S. Chukkapallib, Richard Welburya and Sim K. Singhraoa,∗ aBrain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of Dentistry, University of Central Lancashire, Preston, UK bDepartment of Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, USA Accepted 11 November 2020 Abstract. 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-␤ protin precursor (A␤PP) and tau resulting in the formation of amyloid-␤ 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. Keywords: Alzheimer’s disease, gingipains, periodontal disease, Porphyromonas gingivalis ALZHEIMER’S DISEASE AND ITS and the roles of A␤ plaques and NFTs appear quite ASSOCIATION WITH PERIODONTAL distinct but together they lead to neurodegeneration. DISEASE The hippocampus contains abundant intraneuronal NFTs composed of abnormally phosphorylated tau The presence of extraneuronal amyloid (A␤) protein. According to Braak staging of AD, the plaques and intraneuronal neurofibrillary tangles NFTs spread in the brain in a defined distribution, (NFTs) in the brain, together with defined clinical which allows correlations to be made with the clin- signs of cognitive deficit, form the basis of the diag- ical stages [3]. Early involvement of tau pathology nostic criteria for AD at autopsy [1, 2]. The origins has been described in the subcortical nuclei such as the locus coeruleus and the pons anatomical areas of the brainstem [3, 4]. This anatomical site of the ∗Correspondence to: Sim K. Singhrao, Brain and Behavior Centre, Faculty of Clinical and Biomedical Sciences, School of brain releases norepinephrine in response to emotio- Dentistry, University of Central Lancashire, Preston, UK. Tel.: +44 nal and stress related factors. The locus coeruleus also 0 1772 895137; E-mail: [email protected]. controls the attention and alertness of an individual, ISSN 2542-4823/20/$35.00 © 2020 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0). 502 S. Kanagasingam et al. / Porphyromonas gingivalis Is a Strong Risk Factor for Alzheimer’s Disease so any adverse change in its homeostasis could affect secreted exotoxin known as gingipains that expresses behavior and mood. Notably, the trigeminal gan- cathepsin B proteolytic enzymatic activity, which glion is located adjacent to the locus coeruleus of the enables cleavage of amyloid-␤ protein precursor brainstem [5]. It follows that the brainstem and the (A␤PP), to form A␤ plaques. Furthermore, gingi- periodontium communicate via the trigeminal nerve pains has the potential to disturb tau homeostasis by because tooth related pain is registered in the brain. hyperphosphorylating serine and threonine residues In support, the neurons of the trigeminal nerve five via inflammatory signaling that activate glycogen are known to be distributed within the periodon- synthase kinase-3beta (GSK-3␤). In addition, prote- tal ligament [13]. This provides an important link olytically active gingipains can hydrolyze tau protein between periodontitis and the areas of the brain that to release fragments [12] with the “VQIINK” and are affected early in the progression of AD pathology. “VQIVYK” hexapeptide motifs that are present in Periodontitis is a chronic inflammatory disease the paired helical filaments (PHF) that constitute the which damages the tooth supporting tissues, i.e., gin- NFT lesion. These are significant recent leaps in sci- givae, periodontal ligament, and alveolar bone [6, 7]. entific advances in order to understand the risk factor Bacteria which can instigate changes in a normally involvement of periodontal disease with the develop- symbiotic microbial community to a dysbiotic state ment of AD. are termed ‘keystone pathogens’. Porphyromonas gingivalis (P. gingivalis) is a Gram negative coc- cobacillus shaped bacterium which has long been WHAT MAKES P. GINGIVALIS A RISK established as a keystone pathogen for periodonti- FACTOR FOR AD? tis [6, 7]. This oral commensal becomes pathogenic and can exert its virulence via its endo/exotoxins Inflammation is widely thought to contribute to (surface membrane lipopolysaccharide or LPS, and the cognitive decline in AD [18]. However, periph- gingipains) and capsular polysaccharides that allow eral episodes of inflammation and/or microbial access this bacterium to induce chemokine paralysis of the to the brain and their impact on triggering cerebral host and evade immune recognition, even in low inflammation have largely been ignored. The path- abundance. The compromised host innate and adap- ways for microbial access to the brain are many [19] tive immune responses may be inadequate to control including a leaky blood-brain barrier (BBB). P.gingi- the inflammophilic microbiota and paradoxically, can valis can trigger the peripheral and cerebral immune contribute to connective tissue damage and inflam- responses. Periodontitis can exert its influence indi- matory bone loss [8]. Oral microbes can enter the rectly by sustaining peripheral inflammation. This systemic circulation during transient episodes of bac- together with defective susceptibility genes that nor- teraemia which can occur with daily oral hygiene mally help with clearance of waste from the brain, activities and dental interventions [9]. Periodontal can prime microglial cells into a pro-inflammatory pathogens including P. gingivalis have been detected phenotype [20]. at disparate sites such as the atherosclerotic plaque Other major risk factors for AD are comorbid in [10] and AD brains [11, 12]. Pertinent to this, it the presence of the Apolipoprotein E allele 4 (APOE has been demonstrated in AD transgenic mice that ␧4) susceptibility gene inheritance [21]. One effect is extraction of molar teeth generated release of the related to the decline of cerebral blood flow across the cytotoxic A␤, and triggered neurodegeneration in the lifespan of an individual during normal aging but this locus coeruleus via its connection with the trigemi- effect is greater in subjects with APOE ␧4 suscep- nal nerve five pathway connecting the periodontium tibility gene inheritance [22]. Lack of an adequate [13]. This may provide an explanation for the under- systemic blood flow to the brain in older individu- appreciated concepts such as missing molar teeth and als and those suffering from dementia harboring the their contribution to neuronal loss in AD [14–17]. APOE ␧4 susceptibility gene can precipitate cere- This review will cover some salient aspects of brovascular pathologies such as stroke, small vessel P. gingivalis, the keystone periodontal disease pat- arteriosclerosis, and others [23–25]. In addition, mid- hogen, that makes this bacterium “important” as a dle aged hypertension and diabetes also increase the strong risk factor for developing AD pathophysiol- risk of AD [26]; this risk may be heightened in ogy with an emphasis on the pathways that produce the presence of P. gingivalis oral infection due to hallmark pathology. This is plausible as we now severe periodontitis, which has metabolic implica- have a better understanding of the P. gingivalis tions for an individual’s peripheral and brain health S. Kanagasingam et al. / Porphyromonas gingivalis Is a Strong Risk Factor for Alzheimer’s Disease 503 Fig. 1. The keystone periodontal pathogen, P. gingivalis (P.g), can enter the bloodstream during episodes of transient bacteremia and gain access to the brain via multiple routes including a leaky blood-brain barrier. The microbial invasion triggers the cerebral immune response resulting in neuroinflammation and in the formation of the two diagnostic lesions of AD. Periodontitis can exert its influence indirectly by sustaining peripheral inflammation (blue dotted arrow). This
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