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Authors: Kanagasingam, Shalini | Chukkapalli, Sasanka S. | Welbury, Richard | Singhrao, Sim K.

Article Type: Review Article

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-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. Show more

Keywords: Alzheimer’s disease, gingipains, periodontal disease, Porphyromonas gingivalis

DOI: 10.3233/ADR-200250

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 501-511, 2020

Authors: Singhrao, Sim K. | Harding, Alice | Chukkapalli, Sasanka | Olsen, Ingar | Kesavalu, Lakshmyya | Crean, StJohn

Article Type: Review Article

Abstract: The primary goal of advancement in clinical services is to provide a health care system that enhances an individual’s quality of life. Incidence of diabetes mellitus, cardiovascular disease, and associated dementia coupled with the advancing age of the population, have led to an increase in the worldwide challenge to the healthcare system. In order to overcome these challenges, prior knowledge of common, reliable risk factors and their effectors is essential. Oral health constitutes one such relatively unexplored but indispensable risk factor for aforementioned co-morbidities, in the form of poor oral hygiene and tooth loss during aging. Behavioral traits such as …low education, smoking, poor diet, neglect of oral health, lack of exercise, and hypertension are few of the risk factors that are shared commonly among these conditions. In addition, common genetic susceptibility traits such as the apolipoprotein E gene, together with an individual’s lifestyle can also influence the development of co-morbidities such as periodontitis, atherosclerosis/stroke, diabetes, and Alzheimer’s disease. This review specifically addresses the susceptibility of apolipoprotein E gene allele 4 as the plausible commonality for the etiology of co-morbidities that eventually result from periodontal diseases and ultimately progress to dementia. Show more

Keywords: Alzheimer’s disease, apolipoprotein, atherosclerosis, co-morbidities, dyslipidemia, periodontitis

DOI: 10.3233/JAD150690

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 935-948, 2016

Authors: Poole, Sophie | Singhrao, Sim K. | Chukkapalli, Sasanka | Rivera, Mercedes | Velsko, Irina | Kesavalu, Lakshmyya | Crean, StJohn

Article Type: Research Article

Abstract: Periodontal disease is a polymicrobial inflammatory disease that leads to chronic systemic inflammation and direct infiltration of bacteria/bacterial components, which may contribute to the development of Alzheimer's disease. ApoE-/- mice were orally infected (n = 12) with Porphyromonas gingivalis , Treponema denticola , Tannerella forsythia , and Fusobacterium nucleatum as mono- and polymicrobial infections. ApoE-/- mice were sacrificed following 12 and 24 weeks of chronic infection. Bacterial genomic DNA was isolated from all brain tissues except for the F. nucleatum mono-infected group. Polymerase chain reaction was performed using universal 16 s rDNA primers and species-specific primer sets for each organism …to determine whether the infecting pathogens accessed the brain. Sequencing amplification products confirmed the invasion of bacteria into the brain during infection. The innate immune responses were detected using antibodies against complement activation products of C3 convertase stage and the membrane attack complex. Molecular methods demonstrated that 6 out of 12 ApoE-/- mice brains contained P. gingivalis genomic DNA at 12 weeks (p = 0.006), and 9 out of 12 at 24 weeks of infection (p = 0.0001). Microglia in both infected and control groups demonstrated strong intracellular labeling with C3 and C9, due to on-going biosynthesis. The pyramidal neurons of the hippocampus in 4 out of 12 infected mice brains demonstrated characteristic opsonization with C3 activation fragments (p = 0.032). These results show that the oral pathogen P. gingivalis was able to access the ApoE-/- mice brain and thereby contributed to complement activation with bystander neuronal injury. Show more

Keywords: Alzheimer's disease, chronic periodontitis, inflammation, periodontal bacteria

DOI: 10.3233/JAD-140315

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 67-80, 2015

Authors: Rokad, Farheen | Moseley, Ryan | Hardy, Rowan S. | Chukkapalli, Sasanka | Crean, StJohn | Kesavalu, Lakshmyya | Singhrao, Sim K.

Article Type: Research Article

Abstract: The polymicrobial dysbiotic subgingival biofilm microbes associated with periodontal disease appear to contribute to developing pathologies in distal body sites, including the brain. This study examined oxidative stress, in the form of increased protein carbonylation and oxidative protein damage, in the tumor necrosis factor-α (TNF-α) transgenic mouse that models inflammatory TNF-α excess during bacterial infection; and in the apolipoprotein knockout (ApoE– / – ) mouse brains, following Porphyromonas gingivalis gingival monoinfection. Following 2,4-dinitrophenylhydrazine derivatization, carbonyl groups were detected in frontal lobe brain tissue lysates by immunoblotting and immunohistochemical analysis of fixed tissue sections from the frontotemporal lobe and the hippocampus. …Immunoblot analysis confirmed the presence of variable carbonyl content and oxidative protein damage in all lysates, with TNF-α transgenic blots exhibiting increased protein carbonyl content, with consistently prominent bands at 25 kDa (p  = 0.0001), 43 kDa, and 68 kDa, over wild-type mice. Compared to sham-infected ApoE–/– mouse blots, P. gingivalis -infected brain tissue blots demonstrated the greatest detectable protein carbonyl content overall, with numerous prominent bands at 25 kDa (p  = 0.001) and 43 kDa (p  = 0.0001) and an exclusive band to this group between 30–43 kDa* (p  = 0.0001). In addition, marked immunostaining was detected exclusively in the microvasculature in P. gingivalis -infected hippocampal tissue sections, compared to sham-infected, wild-type, and TNF-α transgenic mice. This study revealed that the hippocampal microvascular structure of P. gingivalis -infected ApoE– / – mice possesses elevated oxidative stress levels, resulting in the associated tight junction proteins being susceptible to increased oxidative/proteolytic degradation, leading to a loss of functional integrity. Show more

Keywords: Hippocampus, infection, microvasculature, oxidative stress/damage, Porphyromonas gingivalis, tight junction proteins

DOI: 10.3233/JAD-170304

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 359-369, 2017

Authors: Kanagasingam, Shalini | von Ruhland, Christopher | Welbury, Richard | Chukkapalli, Sasanka S. | Singhrao, Sim K.

Article Type: Research Article

Abstract: Background: Cleavage of the amyloid-β protein precursor (AβPP) mediated by host secretase enzymes, releases several fragments including amyloid-β (Aβ40 and Aβ42 ). Objective: To determine if Porphyromonas gingivalis conditioned medium cleaved AβPP to release Aβ40 and Aβ42 . Methods: The SH-SY5Y cell line was challenged, in vitro , with P. gingivalis (Pg381) conditioned medium in the presence/absence of cytokines. The cells and their supernatants were assessed for AβPP cleavage fragments by immunoblotting and transmission electron microscopy. Results: Western blotting of the cell lysates with the anti-AβPP C-terminal antibody demonstrated variable molecular weight bands corresponding to full length and fragmented AβPP …in lanes treated with the following factors: Tryptic soy broth (TSB), Pg381, IL-6, Pg381 + IL-1β, and Pg381 + TNF-α. The low molecular weight bands corresponding to the C99 dimerized fragment were observed in the Pg381 and interlukin-6 (IL-6) treated groups and were significantly more intense in the presence of Pg381 with either IL-6 or TNF-α. Bands corresponding to the dimerized C83 fragment were observed with cells treated with TNF-α alone and with Pg381 combined with IL-1β or IL-6 or TNF-α. The anti-Aβ antibody detected statistically significant Aβ40 and Aβ42 , levels when these two Aβ species were pooled across test samples and compared to the untreated group. Electron microscopic examination of the supernatants demonstrated insoluble Aβ40 and Aβ42 . Conclusion: These observations strongly imply that AβPP is an infection responsive protein cleaved via the amyloidogenic pathway on exposure to conditioned medium and in the presence of pro-inflammatory mediators. Show more

Keywords: Amyloid-β, amyloid-βprotein precursor, Porphyromonas gingivalis conditioned medium

DOI: 10.3233/ADR-220029

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 577-587, 2022

Authors: Bahar, Bojlul | Kanagasingam, Shalini | Tambuwala, Murtaza M. | Aljabali, Alaa A.A. | Dillon, Stephanie A. | Doaei, Saeid | Welbury, Richard | Chukkapalli, Sasanka S. | Singhrao, Sim K.

Article Type: Research Article

Abstract: Background: Periodontal disease(s) and metabolic illnesses negatively impact the quality of life and, eventually mental health. Objective: This study investigated the effect of Porphyromonas gingivalis (W83) oral infection on the development of Alzheimer’s disease (AD) pathophysiology in a wild-type obese, diabetic (db/db) mouse model. Methods: The db/db mice were either orally infected with P. gingivalis and Fusobacterium nucleatum or sham infected for 16 weeks. The presence of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) were assessed using a silver impregnation technique and subsequently by immunohistochemistry for tau and neuroinflammation. The mRNA abundance of a panel of 184 genes was performed using …quantitative real-time PCR, and the differentially expressed genes were analyzed by Ingenuity Pathway Analysis. Results: While no Aβ plaques and NFTs were evident by silver impregnation, immunohistochemistry (glial cell markers) of the P. gingivalis -infected mice tissue sections exhibited neuroinflammation in the form of reactive microglia and astrocytes. Anti-tau immunopositivity, in addition to cells, was prominent in thickened axons of hippocampal CA neurons. The mRNA abundance of crucial genes in the insulin signaling pathway (INSR, IGF1, IRS, IDE, PIK3R, SGK1, GYS, GSK3B, AKT1 ) were upregulated, potentially exacerbating insulin resistance in the brain by P. gingivalis oral infection. Increased mRNA abundance of several kinases, membrane receptors, transcription factors, and pro-inflammatory mediators indicated hyperactivation of intracellular cascades with potential for tau phosphorylation and Aβ release in the same infection group. Conclusion: P. gingivalis W83 infection of db/db mice provides a disease co-morbidity model with the potential to reproduce AD pathophysiology with induced periodontal disease. Show more

Keywords: Alzheimer’s disease, diabetes genes, insulin resistance, Porphyromonas gingivalis

DOI: 10.3233/JAD-210465

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1259-1275, 2021