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Poor Oral Health and Its Neurological Consequences: Mechanisms of Porphyromonas gingivalis Involvement in Cognitive Dysfunction

  • Ingar OlsenEmail author
  • Sim K. Singhrao
Microbiology (C Genco, Section Editor)
  • 14 Downloads
Part of the following topical collections:
  1. Topical Collection on Microbiology

Abstract

Purpose of Review

There is an increasing body of evidence from epidemiology and laboratory investigations demonstrating periodontal disease as a risk factor for dementia. In particular, Porphyromonas gingivalis infections in animal models suggest causal associations with Alzheimer’s disease (AD). This review focuses on how P. gingivalis infections promote the incidence of functional loss in AD.

Recent Findings

The risk of the sporadic form of AD doubles when periodontitis persists for ten or more years. AD differs from other forms of dementia in that the clinical signs together with the presence of amyloid-beta (Aβ) plaques and neurofibrillary tangles must be present at autopsy. P. gingivalis oral infections in mice have demonstrated all of the characteristic pathological and clinical features of AD following infection of the brain.

Summary

Multiple factors (inflammation, Aβ oligomers, and bacterial factors) are likely to disrupt neuronal communication channels (synapses) as a plausible explanation for the functional loss.

Keywords

Alzheimer’s disease Periodontitis Interaction P. gingivalis Virulence factors 

Notes

Compliance with Ethical Standards

Conflict of Interest

Ingar Olsen and Sim K. Singhrao each declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Olsen I. From the Acta Prize Lecture 2014: the periodontal-systemic connection seen from a microbiological standpoint. Acta Odontol Scand. 2015;73(8):563–8.  https://doi.org/10.3109/00016357.2015.1007480.CrossRefPubMedGoogle Scholar
  2. 2.
    Olsen I, Singhrao SK. Can oral infection be a risk factor for Alzheimer’s disease? J Oral Microbiol. 2015;7:29143.  https://doi.org/10.3402/jom.v7.29143.CrossRefPubMedGoogle Scholar
  3. 3.
    Olsen I, Singhrao SK, Potempa J. Citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis and Alzheimer’s disease. J Oral Microbiol. 2018;10(1):1487742.  https://doi.org/10.1080/20002297.2018.1487742.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    •• Chen CK, Wu YT, Chang YC. Periodontal inflammatory disease is associated with the risk of Parkinson’s disease: a population-based retrospective matched-cohort study. PeerJ. 2017;5:e3647.  https://doi.org/10.7717/peerj.3647. Reducing periodontitis may modify the risk of developing Parkinson’s disease.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    •• Chen CK, Huang JY, Wu YT, Chang YC. Dental scaling decreases the risk of Parkinson’s disease: a nationwide population-based nested case-control study. Int J Environ Res Public Health. 2018;15(8).  https://doi.org/10.3390/ijerph15081587. First study to show that patients without periodontitis who received dental scaling over 5 consecutive years had a significantly lower risk of developing Parkinson’s disease. CrossRefGoogle Scholar
  6. 6.
    •• Pang S, Li J, Zhang Y, Chen J. Meta-analysis of the relationship between the APOE gene and the onset of Parkinson's disease dementia. Parkinsons Dis. 2018;2018:9497147.  https://doi.org/10.1155/2018/9497147. APOE genotypes, ɛ3/4 and ɛ4/4 may be risk factors for Parkinson’s disease dementia. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    •• Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One. 2010;5(3):e9505.  https://doi.org/10.1371/journal.pone.0009505. Abeta is a hitherto unrecognized antimicrobial peptide that may normally act in the innate immune system. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med. 2016;8(340):340ra72.  https://doi.org/10.1126/scitranslmed.aaf1059.CrossRefPubMedGoogle Scholar
  9. 9.
    •• Park SC, Moon JC, Shin SY, Son H, Jung YJ, Kim NH, et al. Functional characterization of alpha-synuclein protein with antimicrobial activity. Biochem Biophys Res Commun. 2016;478(2):924–8.  https://doi.org/10.1016/j.bbrc.2016.08.052. Alpha-synuclein appears to be a natural antimicrobial peptide in addition to having a role in neurotransmitter release. CrossRefPubMedGoogle Scholar
  10. 10.
    Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, et al. Alzheimer’s disease-associated β-amyloid is rapidly seeded by Herpesviridae to protect against brain infection. Neuron. 2018;99(1):56–63.e3.  https://doi.org/10.1016/j.neuron.2018.06.030.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    •• Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S. Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J Alzheimers Dis. 2013;36(4):665–77.  https://doi.org/10.3233/JAD-121918. The original study confirmed that P. gingivalis lipopolysaccharide reaches the Alzheimer disease brain. CrossRefPubMedGoogle Scholar
  12. 12.
    •• Poole S, Singhrao SK, Chukkapalli S, Rivera M, Velsko I, Kesavalu L, et al. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE−/− mice brains. J Alzheimers Dis. 2015;43(1):67–80.  https://doi.org/10.3233/JAD-140315 P. gingivalis. was able to access the ApoE −/− mice brain contributing to complement activation by bystander neuronal injury. CrossRefGoogle Scholar
  13. 13.
    •• Ilievski V, Zuchowska PK, Green SJ, Toth PT, Ragozzino ME, Le K, et al. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and production amyloid beta in wild type mice. PLoS One. 2018;13(10):e0204941.  https://doi.org/10.1371/journal.pone.0204941. First study to show neurodegeneration and formation of extracellular Aß42 and phosphotau bound to neurofibrillary tangles in young adult wild type mice after repeated application of P. gingivalis. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    •• Wu Z, Ni J, Liu Y, Teeling JL, Takayama F, Collcutt A, et al. Cathepsin B plays a critical role in inducing Alzheimer’s disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice. Brain Behav Immun. 2017;65:350–61.  https://doi.org/10.1016/j.bbi.2017.06.002. Chronic systemic exposure to PgLPS induced AD-like phenotypes, including microglia-mediated neuroinflammation, intracellular Aβ accumulation in neurons and impairment of the learning and memory functions in the middle-aged mice in a CatB-dependent manner. Linked IL-1β involvement in memory deterioration. CrossRefPubMedGoogle Scholar
  15. 15.
    •• Ishida N, Ishihara Y, Ishida K, Tada H, Funaki-Kato Y, Hagiwara M, et al. Periodontitis induced by bacterial infection exacerbates features of Alzheimer’s disease in transgenic mice. NPJ Aging Mech Dis. 2017;3:15.  https://doi.org/10.1038/s41514-017-0015-x. Periodontitis caused by P. gingivalis may exacerbate brain Aβ deposition, leading to increased cognitive impairments, by a mechanism that involves triggering brain inflammation. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    •• Ding Y, Ren J, Yu H, Yu W, Zhou Y. Porphyromonas gingivalis, a periodontitis causing bacterium, induces memory impairment and age-dependent neuroinflammation in mice. Immun Ageing. 2018;15:6.  https://doi.org/10.1186/s12979-017-0110-7. The learning and memory abilities of the middle-aged mice infected with P. gingivalis were impaired. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Primers. 2015;1:15056.  https://doi.org/10.1038/nrdp.2015.56.CrossRefPubMedGoogle Scholar
  18. 18.
    •• Singhrao SK, Harding A, Chukkapalli S, Olsen I, Kesavalu L, Crean S. Apolipoprotein E related co-morbidities and Alzheimer’s disease. J Alzheimers Dis. 2016;51(4):935–48.  https://doi.org/10.3233/JAD150690. The apolipoprotein E gene allele 4 is the plausible commonality for the etiology of co-morbidities that eventually result from periodontal diseases and ultimately progress to mixed pathologies and dementia. CrossRefPubMedGoogle Scholar
  19. 19.
    Li J, Luo J, Liu L, Fu H, Tang L. The genetic association between apolipoprotein E gene polymorphism and Parkinson disease: a meta-analysis of 47 studies. Medicine (Baltimore). 2018;97(43):e12884.  https://doi.org/10.1097/MD.0000000000012884.CrossRefGoogle Scholar
  20. 20.
    • Singhrao SK, Olsen I. Assessing the role of Porphyromonas gingivalis in periodontitis to determine a causative relationship with Alzheimer’s disease. J Oral Microbiol. 2019;11:1563405.  https://doi.org/10.1080/20002297.2018.1563405. Summation of animal studies supporting the P. gingivalis infection link with AD risk factor development. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    •• Yin C, Ackermann S, Ma Z, et al. ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med. 2019;25(3):496–506 Publisher correction: Nat Med. 2019; 25(3): 529. Original study suggesting a new function for the APOE gene as a checkpoint of classical complement activation in AD. CrossRefGoogle Scholar
  22. 22.
    • Rokad F, Moseley R, Hardy RS, Chukkapalli S, Crean S, Kesavalu L, et al. Cerebral oxidative stress and microvasculature defects in TNF-α expressing transgenic and Porphyromonas gingivalis-infected ApoE-/- mice. J Alzheimers Dis. 2017;60(2):359–69.  https://doi.org/10.3233/JAD-170304. 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 hydrolysis of the amyloid precursor protein to generate Aβ in wild type mice infected with P. gingivalis . CrossRefPubMedGoogle Scholar
  23. 23.
    •• Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer's disease. Alzheimers Dement. 2018;14(12):1602–14.  https://doi.org/10.1016/j.jalz.2018.06.3040. The new Antimicrobial Protection Hypothesis reveals brain microbial burden may directly generate β-amyloid deposits, inflammation, and AD progression. This study underpins the role of microbes in the pathogenesis of AD. CrossRefPubMedGoogle Scholar
  24. 24.
    •• Singhrao SK, Chukkapalli S, Poole S, Velsko I, Crean SJ, Kesavalu L. Chronic Porphyromonas gingivalis infection accelerates the occurrence of age-related granules in ApoE−/− mice brains. J Oral Microbiol. 2017;9(1):1270602.  https://doi.org/10.1080/20002297.2016.1270602 ApoE −/− mice showing the earliest inflammation-mediated tissue injury, accompanied by cerebral blood-brain barrier breach. CrossRefGoogle Scholar
  25. 25.
    •• Bowman GL, Dayon L, Kirkland R, Wojcik J, Peyratout G, Severin IC, et al. Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults. Alzheimers Dement. 2018;14(12):1640–50.  https://doi.org/10.1016/j.jalz.2018.06.2857. Blood-brain-barrier breakdown is associated with cognitive decline and inflammation in non-demented elders. CrossRefPubMedGoogle Scholar
  26. 26.
    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–6 Erratum in: Science 2002; 297(5590): 2209.CrossRefGoogle Scholar
  27. 27.
    •• Boche D, Donald J, Love S, Harris S, Neal JW, Holmes C, et al. Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer’s disease. Acta Neuropathol. 2010;120(1):13–20. Removal of Abeta from the brain via immunisation does not improve memory. CrossRefGoogle Scholar
  28. 28.
    • Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30(4):572–80. Origins of the synaptic loss theory to explain cognitive deficit. CrossRefGoogle Scholar
  29. 29.
    • Masliah E, Hansen L, Albright T, Mallory M, Terry RD. Immunoelectron microscopic study of synaptic pathology in Alzheimer’s disease. Acta Neuropathol. 1991;81(4):428–33. Provides evidence to support the synaptic loss theory. CrossRefGoogle Scholar
  30. 30.
    •• Cline EN, Bicca MA, Viola KL, Klein WL. The amyloid-β oligomer hypothesis: beginning of the third decade. J Alzheimers Dis. 2018;64(s1):S567–610.  https://doi.org/10.3233/JAD-179941. Revised Amyloid-β oligomer theory. Soluble Aβ oligomers accumulate in an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    •• Olsen I, Singhrao SK. Inflammasome involvement in Alzheimer’s disease. J Alzheimers Dis. 2016;54(1):45–53. This review supports the mechanism of P. gingivalis infection promoting cognitive deficit (see ref 52). CrossRefGoogle Scholar
  32. 32.
    Gatz M, Mortimer JA, Fratiglioni L, Johansson B, Berg S, Reynolds CA, et al. Potentially modifiable risk factors for dementia in identical twins. Alzheimers Dement. 2006;2:110–7.CrossRefGoogle Scholar
  33. 33.
    Stein PS, Desrosiers M, Donegan SJ, Yepes JF, Kryscio RJ. Tooth loss, dementia and neuropathology in the Nun study. J Am Dent Assoc. 2007;138(10):1314–22, quiz 1381-2.CrossRefGoogle Scholar
  34. 34.
    Stein PS, Kryscio RJ, Desrosiers M, Donegan SJ, Gibbs MB. Tooth loss, apolipoprotein E, and decline in delayed word recall. J Dent Res. 2010;89(5):473–7.  https://doi.org/10.1177/0022034509357881.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kamer AR, Craig RG, Pirraglia E, Dasanayake AP, Norman RG, Boylan RJ, et al. TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer’s disease patients and normal subjects. J Neuroimmunol. 2009;216(1–2):92–7.  https://doi.org/10.1016/j.jneuroim.2009.08.013.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    • Farhad SZ, Amini S, Khalilian A, Barekatain M, Mafi M, Barekatain M, et al. The effect of chronic periodontitis on serum levels of tumor necrosis factor-alpha in Alzheimer disease. Dent Res J (Isfahan). 2014;11(5):549–52. Not all of the AD cases they examined at the clinical level co-existed with periodontitis. Google Scholar
  37. 37.
    •• Sparks Stein P, Steffen MJ, Smith C, Jicha G, Ebersole JL, Abner E, et al. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease. Alzheimers Dement. 2012;8(3):196–203.  https://doi.org/10.1016/j.jalz.2011.04.006. A laboratory study that agreed with the epidemiological study of Chen et al. (ref 38) for the 10 year timeline in risk development following periodontitis diagnosis. CrossRefPubMedGoogle Scholar
  38. 38.
    •• Chen CK, Wu YT, Chang YC. Association between chronic periodontitis and the risk of Alzheimer’s disease: a retrospective, population-based, matched-cohort study. Alzheimers Res Ther. 2017;9(1):56.  https://doi.org/10.1186/s13195-017-0282-6. A 10-year CP exposure was associated with a 1,707-fold increase in the risk of developing AD. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Stewart R, Weyant RJ, Garcia ME, Harris T, Launer LJ, Satterfield S, et al. Adverse oral health and cognitive decline: the health, aging and body composition study. J Am Geriatr Soc. 2013;61(2):177–84.  https://doi.org/10.1111/jgs.12094.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kaye EK, Valencia A, Baba N, Spiro A 3rd, Dietrich T, Garcia RI. Tooth loss and periodontal disease predict poor cognitive function in older men. J Am Geriatr Soc. 2010;58(4):713–8.  https://doi.org/10.1111/j.1532-5415.2010.02788.x.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    • Daly B, Thompsell A, Sharpling J, Rooney YM, Hillman L, Wanyonyi KL, et al. Evidence summary: the relationship between oral health and dementia. Br Dent J. 2018;223(11):846–53.  https://doi.org/10.1038/sj.bdj.2017.992. Poor oral hygiene is associated with dementia, and more so amongst people in advanced stages of the disease. CrossRefPubMedGoogle Scholar
  42. 42.
    • de Souza RT, Fabri GM, Nitrini R, Anghinah R, Teixeira MJ, de Siqueira JT, et al. Oral infections and orofacial pain in Alzheimer’s disease: a case-control study. J Alzheimers Dis. 2014;38(4):823–9.  https://doi.org/10.3233/JAD-131283. An interventional study on the periodontal treatment in AD patients indicated a plausible causal relationship in demented individuals. CrossRefGoogle Scholar
  43. 43.
    • Emanuel R, Sorensen A. A study of oral health prevention behaviours for patients with early stage dementia. Br Dent J. 2018;224(1):38–42.  https://doi.org/10.1038/sj.bdj.2018.5. There was clearly scope for improving oral health education and prevention for dementia patients. CrossRefPubMedGoogle Scholar
  44. 44.
    • Hajishengallis G. Immune evasion strategies of Porphyromonas gingivalis. J Oral Biosci. 2011;53(3):233–40. Exploitation of Toll-like receptor-2, complement receptor 3, C5a anaphylatoxin receptor, and CXC-chemokine receptor 4 by P. gingivalis allows the pathogen to escape elimination, obtain nutrients, and collaterally inflict periodontal tissue injury. CrossRefGoogle Scholar
  45. 45.
    • Hajishengallis G, Lambris JD. Complement and dysbiosis in periodontal disease. Immunobiology. 2012;217(11):1111–6.  https://doi.org/10.1016/j.imbio.2012.07.007. P. gingivalis expresses C5 convertase-like enzymatic activity and adeptly exploits complement-TLR crosstalk to subvert host defenses and escape elimination. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Hajishengallis G, Abe T, Maekawa T, Hajishengallis E, Lambris JD. Role of complement in host-microbe homeostasis of the periodontium. Semin Immunol. 2013;25(1):65–72.  https://doi.org/10.1016/j.smim.2013.04.004.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hussain M, Stover CM, Dupont A. P. gingivalis in periodontal disease and atherosclerosis - scenes of action for antimicrobial peptides and complement. Front Immunol. 2015;6:45.  https://doi.org/10.3389/fimmu.2015.00045.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Olsen I, Hajishengallis G. Major neutrophil functions subverted by Porphyromonas gingivalis. J Oral Microbiol. 2016;8:30936.  https://doi.org/10.3402/jom.v8.30936.CrossRefPubMedGoogle Scholar
  49. 49.
    Olsen I, Singhrao SK, Osmundsen H. Periodontitis, pathogenesis and progression: miRNA-mediated cellular responses to Porphyromonas gingivalis. J Oral Microbiol. 2017;9(1):1333396.  https://doi.org/10.1080/20002297.2017.1333396.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    •• Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;5:eaau3333. This study has provided the strongest evidence for causal links of P. gingivalis infection with AD. It has raised the vital awareness in periodontitis and AD developmental links. It offers hope for a future treatment via gingipain inhibiting drugs. CrossRefGoogle Scholar
  51. 51.
    •• Llorente P, Kristen H, Sastre I, Toledano-Zaragoza A, Aldudo J, Recuero M, et al. A free radical-generating system regulates amyloid oligomers: involvement of cathepsin B. J Alzheimers Dis. 2018;66:1397–408.  https://doi.org/10.3233/JAD-170159. Cathepsin B participates in the changes of amyloid oligomer induced by mild oxidative stress. This supports the oxidative stress related damage following P. gingivalis infection as reported in ref 22. CrossRefPubMedGoogle Scholar
  52. 52.
    •• Zhang J, Yu C, Zhang X, Chen H, Dong J, Lu W, et al. Porphyromonas gingivalis lipopolysaccharide induces cognitive dysfunction, mediated by neuronal inflammation via activation of the TLR4 signaling pathway in C57BL/6 mice. J Neuroinflammation. 2018;15(1):37.  https://doi.org/10.1186/s12974-017-1052-x. Offer a mechanism of how P. gingivalis -LPS-induced neuroinflammation plays an important role in cognitive impairment. This reference complements the review by Olsen and Singhrao ref 31. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Imamura T. The role of gingipains in the pathogenesis of periodontal disease. J Periodontol. 2003;74(1):111–8.CrossRefGoogle Scholar
  54. 54.
    •• Vasek MJ, Garber C, Dorsey D, et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature. 2016;534:538–43. Original study implicating classical complement activation in AD through overt pruning activity in microglia. A novel mechanistic viewpoint of cognitive deficit. CrossRefGoogle Scholar
  55. 55.
    Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci. 2005;25:9275–84.CrossRefGoogle Scholar
  56. 56.
    Tanaka S, Ide M, Shibutani T, Ohtaki H, Numazawa S, Shioda S, et al. Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats. J Neurosci Res. 2006;83:557–66.CrossRefGoogle Scholar
  57. 57.
    Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun. 2008;18:223–30.Google Scholar
  58. 58.
    • Henry CJ, Huang Y, Wynne AM, Godbout JP. Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav Immun. 2009;23(3):309–17. Implicates LPS with release of IL-1β and intracerebral inflammation. CrossRefGoogle Scholar
  59. 59.
    • Bellinger FP, Madamba S, Siggins GR. Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus. Brain Res. 1993;628:227–34. Implicate IL-1β in cognitive deficit. CrossRefGoogle Scholar
  60. 60.
    Mishra A, Kim HJ, Shin AH, Thayer SA. Synapse loss induced by interleukin-1beta requires pre- and post-synaptic mechanisms. J NeuroImmune Pharmacol. 2012;7(3):571–8.  https://doi.org/10.1007/s11481-012-9342-7.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21(3):383–421.CrossRefGoogle Scholar
  62. 62.
    Allen HB. Alzheimer’s disease: assessing the role of spirochetes, biofilms, the immune system, and amyloid-β with regard to potential treatment and prevention. J Alzheimers Dis. 2016;53(4):1271–6.  https://doi.org/10.3233/JAD-160388.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Singhrao SK, Neal JW, Rushmere NK, Morgan BP, Gasque P. Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis. Am J Pathol. 2000;157(3):905–18.CrossRefGoogle Scholar
  64. 64.
    Wingrove JA, DiScipio RG, Chen Z, Potempa J, Travis J, Hugli TE. Activation of complement components C3 and C5 by a cysteine proteinase (gingipain-1) from Porphyromonas (Bacteroides) gingivalis. J Biol Chem. 1992;267(26):18902–7.PubMedGoogle Scholar
  65. 65.
    Popadiak K, Potempa J, Riesbeck K, Blom AM. Biphasic effect of gingipains from Porphyromonas gingivalis on the human complement system. J Immunol. 2007;178(11):7242–50.CrossRefGoogle Scholar
  66. 66.
    Potempa M, Potempa J, Okroj M, Popadiak K, Eick S, Nguyen KA, et al. Binding of complement inhibitor C4b-binding protein contributes to serum resistance of Porphyromonas gingivalis. J Immunol. 2008;181(8):5537–44.CrossRefGoogle Scholar
  67. 67.
    Slaney JM, Curtis MA. Mechanisms of evasion of complement by Porphyromonas gingivalis. Front Biosci. 2008;13:188–96.CrossRefGoogle Scholar
  68. 68.
    Wang M, Krauss JL, Domon H, Hosur KB, Liang S, Magotti P, et al. Microbial hijacking of complement-toll-like receptor crosstalk. Sci Signal. 2010;3(109):ra11.  https://doi.org/10.1126/scisignal.2000697.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    • Olsen I, Singhrao SK. Genetic defects, complement and Porphyromonas gingivalis immune subversion in Alzheimer’s disease. J Oral Microbiol. 2019, submitted. P. gingivalis is a keystone pathogen for periodontitis and its co-morbidities because of the mastery of this bacterium at subverting selective steps in the immune system for effective dysbiosis, which in turn amplifies altered gene functions in Alzheimer’s disease. Google Scholar
  70. 70.
    • Bielecka E, Scavenius C, Kantyka T, Jusko M, Mizgalska D, Szmigielski B, et al. Peptidyl arginine deiminase from Porphyromonas gingivalis abolishes anaphylatoxin C5a activity. J Biol Chem. 2014;289(47):32481–7.  https://doi.org/10.1074/jbc.C114.617142. In the context of previous studies, which showed crosstalk between C5aR and Toll-like receptors, and enhanced arthritis development in mice infected with PPAD-expressing P. gingivalis , a crucial role of PPAD in the virulence of P. gingivalis was supported. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    • Liu Y, Wu Z, Nakanishi Y, Ni J, Hayashi Y, Takayama F, et al. Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice. Sci Rep. 2017;7(1):11759.  https://doi.org/10.1038/s41598-017-12173-1. The authors provide the first evidence that Rgp and Kgp cooperatively contribute to the P. gingivalis -induced cell migration and expression of proinflammatory mediators through the activation of protease-activated receptor 2. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Choi JW, Kim SC, Hong SH, Lee HJ. Secretable small RNAs via outer membrane vesicles in periodontal pathogens. J Dent Res. 2017;96:458–66.  https://doi.org/10.1177/0022034516685071.CrossRefPubMedGoogle Scholar
  73. 73.
    • Singhrao SK, Olsen I. Are Porphyromonas gingivalis outer membrane vesicles, microbullets for sporadic Alzheimer’s disease manifestation? J Alzheimers Dis Rep. 2018;1:1–10.  https://doi.org/10.3233/ADR-180080. Bacterial cultures and established oral biofilms generate vast numbers of microvesicles and P. gingivalis outer membrane vesicles encase key virulence factors (LPS, gingipains, capsule, fimbriae) as though they are complete destructive "microbullets" when shed in the host. CrossRefGoogle Scholar
  74. 74.
    Schertzer JW, Whiteley M. Microbial communication superhighways. Cell. 2011;144(4):469–70.  https://doi.org/10.1016/j.cell.2011.02.001.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    •• Adamowicz K, Wang H, Jotwani R, Zeller I, Potempa J, Scott DA. Inhibition of GSK3 abolishes bacterial-induced periodontal bone loss in mice. Mol Med. 2012;18:1190–6.  https://doi.org/10.2119/molmed.2012.00180. This study confirms the relevance of prior in vitro phenomena and establish GSK3 as a novel, efficacious therapeutic preventing periodontal disease progression in a susceptible host. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Wang H, Brown J, Martin M. Glycogen synthase kinase 3: a point of convergence for the host inflammatory response. Cytokine. 2011;53:130–40.CrossRefGoogle Scholar
  77. 77.
    Baek H, Ye M, Kang GH, Lee C, Lee G, Choi DB, et al. Neuroprotective effects of CD4+CD25+Foxp3+ regulatory T cells in a 3xTg-AD Alzheimer’s disease model. Oncotarget. 2016;7(43):69347–57.  https://doi.org/10.18632/oncotarget.12469.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Yang J, Wu J, Liu Y, Huang J, Lu Z, Xie L, et al. Porphyromonas gingivalis infection reduces regulatory T cells in infected atherosclerosis patients. PLoS One. 2014;9(1):e86599.  https://doi.org/10.1371/journal.pone.0086599.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Gonçalves LS, Ferreira SM, Silva A Jr, Villoria GE, Costinha LH, Souto R, et al. Association of T CD4 lymphocyte levels and subgingival microbiota of chronic periodontitis in HIV-infected Brazilians under HAART. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97(2):196–203.CrossRefGoogle Scholar
  80. 80.
    Emery DC, Shoemark DK, Batstone TE, Waterfall CM, Coghill JA, Cerajewska TL, et al. 16S rRNA next generation sequencing analysis shows bacteria in Alzheimer’s post-mortem brain. Front Aging Neurosci. 2017;9:195.  https://doi.org/10.3389/fnagi.2017.0019.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Oral Biology, Faculty of DentistryUniversity of OsloOsloNorway
  2. 2.Dementia and Neurodegenerative Diseases Research Group, Faculty of Clinical and Biomedical Sciences, School of DentistryUniversity of Central LancashirePrestonUK

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