|
 
 |
| REVIEW |
|
| Year : 2021 | Volume
: 12
| Issue : 4 | Page : 174-178 |
|
Infection of Porphyromonas gingivalis in Alzheimer’s Disease and the Suppression of Immunity
Citra Feriana Putri1, Endang Winiati Bachtiar2
1 Department of Oral Biology, Faculty of Dentistry, Universitas Syiah Kuala, Banda Aceh, Indonesia
2 Department of Oral Biology, Oral Sciences Research Center, Faculty of Dentistry, Universitas Indonesia, Indonesia
| Date of Submission | 14-Mar-2021 |
| Date of Decision | 27-Aug-2021 |
| Date of Acceptance | 18-Sep-2021 |
| Date of Web Publication | 21-Dec-2021 |
Correspondence Address:
Endang Winiati Bachtiar
Department of Oral Biology, Oral Sciences Research Center, Faculty of Dentistry, Universitas Indonesia, Jakarta Pusat, DKI Jakarta 10430
Indonesia
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/denthyp.denthyp_38_21
Alzheimer disease is one of the most frequent neurodegenerative diseases. Porphyromonas gingivalis is the key pathogen of chronic periodontitis, and it has a virulence factor known as gingipain. Gingipain is a proteolytic enzyme capable of penetrating the blood–brain barrier to reach the brain’s center of cognition. Gingipain that reaches the brain is suspected of having a relationship with an amyloid-beta plaque and neurofibrillary tangle, which play a critical role in the formation of Alzheimer disease. These bacteria may also suppress the immune system by reducing cytokine tumor growth factor (TGF-beta) and Interferon (IFN-gamma) and imbalance of Th17/Treg (Regulatory T cells). Besides that, the involvement of P. gingivalis in the brain may trigger neuroinflammation and lead to neuron defect and worsen Alzheimer disease. This review aims to discuss the correlation between P. gingivalis and the development of Alzheimer disease.
Keywords: Alzheimer disease, gingipain, neuroinflammation, Porphyromonas gingivalis, systemic inflammation
How to cite this article:
Putri CF, Bachtiar EW. Infection of Porphyromonas gingivalis in Alzheimer’s Disease and the Suppression of Immunity. Dent Hypotheses 2021;12:174-8 |
| Introduction | |  |
Alzheimer’s disease is a neurodegenerative disease that occurs in the elderly group. According to the Alzheimer’s Association in 2015, around 5 million people in the world have Alzheimer at the age of 65 years old and as many as 200,000 people have Alzheimer’s before the age of 65, and it is predicted that the number of people with Alzheimer will continue to increase by 1 million per year.[1],[2] In Indonesia, according to the Ministry of Health of the Republic of Indonesia, the number of people with Alzheimer in 2013 reached 1 million.[3] The symptoms of Alzheimer disease include: memory problems, difficulty focusing, disorientation, difficulty communicating, withdrawing from relationships, changes in behavior and personality, and difficulty understanding visuospatial.[3] Dr. Alois Alzheimer, who first discovered this disease, stated that there were amyloid and neurofibrillary plaque accumulation (neurofibrillary tangle, NFT) in the brain autopsy of Alzheimer patients, and it was thought to be the main cause of this disease. NFT in the brain is due to systemic inflammation. A chronic systemic inflammatory response is thought to be related to the emergence of Alzheimer disease.[2],[4],[5]
Periodontitis is a chronic disease and is known to trigger the phenomenon of neuroinflammation in patients with Alzheimer. Kamer et al.[6] show that patients with periodontal disease have more beta-amyloid in the brain than patients without periodontal disease. Bacteria that induce host inflammatory response can affect brain function, especially in elderly patients, and trigger the occurrence of neurodegenerative processes.[5],[6] Periodontal bacteria can also invade the brain and activate pro-inflammatory cytokines in the central nervous system homeostasis.[5]
Porphyromonas gingivalis is a major pathogen that causes periodontitis. These bacteria can spread to the arteries, placenta, liver, and brain. P. gingivalis has the main virulence factor known as gingipain, which consists of arginine A (RgpA), arginine B (RgpB), and lysine (Kgp). This virulence factor can manipulate the immune system, cause immunosuppression, tissue damage, and induce neuronal damage.[7] The immunosuppression induced by gingipain and the immunosuppression condition in elderly may trigger neurodegenerative processes.[8] Therefore, this paper discussed the relationship of P. gingivalis infection with Alzheimer disease.
| Methodology | | |
Literature search
Online literature searches were performed using keywords: Porphyromonas gingivalis, gingipain, virulence factor of Porphyromonas gingivalis, pathogenesis, neurons, Alzheimer disease, cognitive dysfunction, immunopathogenesis, and neuroinflammation. The search process was obtained from databases: PubMed, EMBASE, and Current Contents Search (Science Citation Index, SCOPUS, and SCHOLAR). The databases used were the data of the previous 10 years. Related articles published in several journals and textbooks were also considered for review. Then the data was reviewed from September 2020 to December 2020.
Selected literature criteria
Three reviewers examined blindly for inclusion criteria and study quality. All studies published in the previous 10 years that discuss the role of P. gingivalis in Alzheimer disease or those described above were included in this study. Studies that did not clearly explain the ingredients and methods were excluded from the study. Studies that did not use English were also excluded from this study.
Statistical method
The Cohen’s kappa value was used to get an inter-observer agreement value of 0.60 (95% CI 0.52–0.69). This value was categorized as moderate against substance agreement among reviewers.
Alzheimer disease
Alzheimer disease is the most common form of dementia caused by a disease in the brain due to disruption in brain function. This disease often attacks older adults and is a significant health problem in geriatric subjects throughout the world.[9]
The incidence of Alzheimer disease significantly increases with age and reaches almost 50% in people aged 85 years.[10] In Southeast Asia, 6.38% of people with Alzheimer’s disease over the age of 60 years.[11] In Indonesia, according to the Ministry of Health of the Republic of Indonesia, the number of people living with Alzheimer in 2013 reached 1 million people and is predicted to double by the year 2030.[3]
Signs and symptoms of Alzheimer disease are progressive impairments in cognitive abilities, followed by impaired decision-making and other language and psychological disabilities.[12] Patients can also experience difficulties when shopping, differentiating money, as well as daily navigation routes. Anxiety can also occur in Alzheimer patients. These signs and symptoms will get worse along with the severity of the disease.[13],[14]
Knowledge of how P. gingivalis can trigger Alzheimer’s disease will benefit prevention strategies through the development of molecular or anti-gingipain vaccines.
The etiopathogenesis of Alzheimer disease
Till date, there has not been any appropriate model to reveal the pathophysiology of this disease. Key events in the development of Alzheimer’s disease is the formation of beta-amyloid plaques and NFT from tau proteins. This protein causes disruption of communication between nerve cells synapses and neuronal degeneration. The result of protein degradation by the amyloid b-secretase enzyme will form beta-amyloid plaques between neuron cells.[15] Some theories predict that beta-amyloid plaque formation and NFT can be induced by systemic inflammatory conditions that cause nerve cell damage that triggers Alzheimer disease. The formation of beta-amyloid plaque and NFT causes abnormalities in the process of communication of neuron cells.[7],[10],[16]
Beta-amyloid plaque is derived from amyloid precursor protein (APP) which is in the neuronal cell membrane. In Alzheimer disease, the enzyme that degrades APP is the β-secretase enzyme and produces an insoluble amyloid protein. The more amyloid protein cut by the β-secretase enzyme, and then these proteins will combine to form a plaque between neuron cells and are called beta-amyloid plaques. Deposition of beta-amyloid plaques between neuronal cells will inhibit the release and capture of neurotransmitters between neuron cells. This condition may disrupt the delivery of information in the brain, triggering Alzheimer disease.[6],[15],[17],[18]
A chronic disease that occurs in older people can increase the amount of beta-amyloid plaque in the brain. Inflammation that activates cerebral glial cells due to bacterial infection also causes the increase in beta-amyloid plaque in the brain.[6],[15],[16],[18]
NFT is also known to play a role in forming Alzheimer’s disease. Neuron cells have microtubules or cytoskeletons composed of tau proteins. As the tau protein gets dissociated, the microtubules in neuron cells are also damaged. The dissociated tau protein will combine to form a tangle called the NFT. Damage to microtubules in neuron cells causes the delivery of essential nutrients into neuron cells to be disrupted, resulting in neuronal cell death.[13]
Porphyromonas gingivalis
P. gingivalis is a pathogen that plays a role in the pathogenesis of periodontal disease. In addition, about 40% to 100% of adult patients with periodontitis are known to present due to these opportunistic bacteria’s infections.[19],[20]
P. gingivalis are nonmotile, saccharolytic, gram-negative rod-shaped obligate anaerobic bacteria [Figure 1].[22] These bacteria will form a black colony on the blood agar plates and need iron for growth. This condition occurs in bacterial culture for 6 to 10 days and will form heme accumulation of blood hemoglobin in the blood agar plate, causing the colony to turn black.[23],[24]
The primary habitat for P. gingivalis is in the subgingival sulcus of the human oral cavity. P. gingivalis also become a secondary colonizer at the dental plaque formation stage and adhere to Streptococcus gordonii and Prevotella intermedia as primary plaque forming plaque colonizers.[21],[24]
Virulence factor of P. gingivalis
P. gingivalis release the virulence factor to penetrate the gingiva and cause direct or indirect tissue damage due to the inflammatory response. P. gingivalis virulence factors are used to form colonies, avoid the host immune system, and initiate tissue damage.[7],[24],[25]
P. gingivalis survive and reproduce in the host tissue by protecting themselves with external protective material to avoid the immune system before forming a colony. These bacteria release virulence factors such as fimbriae, capsules, lipopolysaccharides (LPS), hemagglutinin, gingipain, membrane protein, and membrane vesicles. Changes influence the expression of virulence factors in the environment outside the periodontal. If activated on the host that benefits it, this virulence factor can cause rapid and massive destruction of periodontal tissue, bone resorption, induce cytokine production, and inhibit host protection mechanisms.[7],[25]
P. gingivalis has fimbriae A (FimA), which functions as a virulence factor attached to subgingival plaque early colonizer groups Streptococcus and Actinomyces species on the tooth root surface. FimA is one of the virulence factor in P. gingivalis for the attachment of this bacterium to the gingival epithelium via integrin receptor. FimA can also bind to fibrinogen, fibronectin, salivary proline-rich protein, and lactoferrin.[26],[27]
LPS from P. gingivalis contribute to alveolar bone resorption by activating osteoclasts. This virulence factor also causes bone resorption by inducing cytokine secretion such as IL-β and tumor necrosis of the abscess and PGE2. Lipid A from P. gingivalis has a unique structure, in which the nonphosphorylated tetra-acyl form of lipid A is inert to the activation of Toll-like receptor 4 (TLR 4) so that this bacterium can avoid the immune system.[26],[28]
The most important protease is gingipain which consists of RgpA and RgpB (arginine), and Kgp (lysine). This enzyme’s specifications are very broad, including destroying the structure of host proteins such as collagen, fibronectin, and laminin. This virulence factor also degrades tissue inhibitors for matrixproteinase (MMP).[24],[29],[30]
The mechanism of the association between P. gingivalis infection and Alzheimer disease
The condition of oral biofilm dysbiosis can affect the brain’s normal functioning and potentially cause depressive damage and the development of dementia. When entered into the bloodstream, these bacteria can reach other organs such as the heart and brain.[16],[24],[31]
Gingipain, a protease enzyme from P. gingivalis, can damage blood vessel endothelium by degrading tight junctions in cells, causing loss of blood–brain barrier (BBB) integrity. Impaired BBB integrity allows these bacteria to enter the brain and damage neuron cells and activate the formation of beta-amyloid plaques and NFT.[16],[24]
The gingipain protease enzyme owned by the P. gingivalis can also prevent it from invading the host immune system while in the bloodstream. This virulence factor works to suppress the amount of interleukin-2 so that it causes differences in the response of cytokines to the immune system and affects the balance of T-helper 17 cells.[8],[32]
Research conducted by Dominy et al. found gingipain R2 (RgpB) in the hippocampus and gingipain Lys (Kgp) in the cerebral cortex of Alzheimer patients. The study also reported P. gingivalis bacteria in the brain by detecting the hmuY gene in the cerebral cortex and cerebrospinal fluid in Alzheimer patients. The cerebral cortex and hippocampus are parts of the brain that function as a person’s cognitive controller. Therefore, damage to this area can cause Alzheimer disease.[8],[30],[33]
The presence of P. gingivalis or its virulence factors in the brain will be captured as antigens by microglia cells as an antigen-presenting cell. TLR4 and CD14 in microglia will bind to the antigen and then release the IL-1β inflammatory mediator. This inflammatory mediator then binds to IL-1R in neuron cells and increases the activity of cathepsin B in lysosomes. This condition might trigger the formation of beta-amyloid plaque in the brain. A continuous increase in beta-amyloid plaque might influence the tau protein’s hyperphosphorylation in intracellular neurons to form a NFT. Activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) cells due to the inflammatory response of antigens by microglia cells also releases the enzyme glycogen synthase-3β, which plays a role in the formation of NFT [Figure 2].[8],[34],[35] | Figure 2 The mechanism of the association between Porphyromonas gingivalis infection and Alzheimer disease
Click here to view |
Prevention of Alzheimer through the biomolecular approach
Several studies have revealed a possible correlation between P. gingivalis infection and the incidence of Alzheimer disease. P. gingivalis involvement with Alzheimer can occur through two mechanisms, namely, P. gingivalis bacteremia to the brain which causes an inflammatory response in the brain. It triggers amyloid plaque formation and the release of inflammatory mediators from periodontitis to systemic inflammatory circulation that can reach neuron cells and trigger beta-amyloid plaque formation.[6],[35]
Prevention of Alzheimer disease is not only done by maintaining oral hygiene but also through biomolecular prevention. A small molecule that can inhibit the release of gingipain is being developed by Dominy et al. and was first published in 2019.[30] The COR271 Kgp inhibitor molecule administered orally in mice effectively reduces P. gingivalis infection in the brain and prevents internal disruption in the hippocampus. Another molecule, COR388, which functions to inhibit gingipain, is still in an experimental stage.[30]
| Conclusion | | |
The virulence factors of P. gingivalis can manipulate the immune system and cause immunosuppression, tissue damage, and induce neuronal damage. Immunosuppression induced by gingipain, and the immunosuppression condition in the elderly trigger neurodegenerative processes. Bacteremia causes bacteria to move to the BBB area in the brain.
Financial support and sponsorship
This study was supported by the PUTI Grant from Universitas Indonesia (Grant: NKB-4823/UN2.RST/HKP.05.00/2020).
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Patterson C. World Alzheimer Report 2018: the state of the art of dementia research. Alzheimer’s Disease International 2018:48. https://apo.org.au/node/260056  |
| 2. | Kumar A, Singh A. A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep 2015;67:195-203. |
| 3. | |
| 4. | Delwel S, Binnekade TT, Perez R, Hertogh C, Scherder EJA, Lobbezoo F. Oral hygiene and oral health in older people with dementia: a comprehensive review with focus on oral soft tissues. Clin Oral Investig 2018;22:93-108. |
| 5. | Teixeira FB, Saito MT, Matheus FC et al. Periodontitis and Alzheimer’s disease: a possible comorbidity between oral chronic inflammatory condition and neuroinflammation. Front Aging Neurosci 2017;9:327. |
| 6. | Kamer AR, Pirraglia E, Tsui W et al. Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiol Aging 2015;36:627-33. |
| 7. | Pritchard AB, Crean S, Olsen I, Singhrao SK. Periodontitis, microbiomes and their role in Alzheimer’s disease. Front Aging Neurosci 2017;9:336. |
| 8. | Olsen I, Taubman MA, Singhrao SK. Porphyromonas gingivalis suppresses adaptive immunity in periodontitis, atherosclerosis, and Alzheimer’s disease. J Oral Microbiol 2016;8:33029. |
| 9. | Abbayya K, Puthanakar NY, Naduwinmani S, Chidambar YS. Association between periodontitis and Alzheimer’s disease. N Am J Med Sci 2015;7:241-6. |
| 10. | Leyhe T, Reynolds CF 3rd, Melcher T et al. A common challenge in older adults: classification, overlap, and therapy of depression and dementia. Alzheimers Dement 2017;13:59-71. |
| 11. | Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 2013;9:63-75.e2. |
| 12. | Dening T, Sandilyan MB. Dementia: definitions and types. Nurs Stand 2015;29:37-42. |
| 13. | Picanco LC, Ozela PF, Brito MdFdB et al. Alzheimer disease: a review from the pathophysiology to diagnosis, new perspectives for pharmacological treatment. Curr Med Chem 2018;25:3141-59. |
| 14. | Li R, Cui J, Shen Y. Brain sex matters: estrogen in cognition and Alzheimer’s disease. Mol Cell Endocrinol 2014;389:13-21. |
| 15. | Wang J, Gu BJ, Masters CL, Wang YJ. A systemic view of Alzheimer disease − insights from amyloid-beta metabolism beyond the brain. Nat Rev Neurol 2017;13:612-23. |
| 16. | Harding A, Gonder U, Robinson SJ, Crean S, Singhrao SK. Exploring the association between Alzheimer’s disease, oral health, microbial endocrinology and nutrition. Front Aging Neurosci 2017;9:398. |
| 17. | Kubota T, Maruyama S, Abe D et al. Amyloid beta (A4) precursor protein expression in human periodontitis-affected gingival tissues. Arch Oral Biol 2014;59:586-94. |
| 18. | Pujol-Pina R, Vilaprinyo-Pascual S, Mazzucato R et al. SDS-PAGE analysis of Aβ oligomers is disserving research into Alzheimer s disease: appealing for ESI-IM-MS. Sci Rep 2015;5:14809. |
| 19. | Sochocka M, Donskow-Lysoniewska K, Diniz BS, Kurpas D, Brzozowska E, Leszek J. The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer’s disease: a critical review. Mol Neurobiol 2019;56:1841-51. |
| 20. | Griffen AL, Becker MR, Lyons SR, Moeschberger ML, Leys LJ. Prevalence of Porphyromonas gingivalisand periodontal health status. J Clin Microbiol 1998;36:3239-42. |
| 21. | Bender P, Egger A, Westermann M et al. Expression of human and Porphyromonas gingivalis glutaminyl cyclases in periodontitis and rheumatoid arthritis: a pilot study. Arch Oral Biol 2019;97:223-30. |
| 22. | Marsh PD, Martin MV. Oral Microbiology. Churchill Livingstone; Imprint: Churchill Livingstone. Published Date: 29th April 2009. p. 232. |
| 23. | Stein PS, Desroslers M, Donogan SJ, Yepes FF, Krysclo RJ. Tooth loss, dementia and neuropathology in the Nun study. J Am Dent Assoc 2007;138:1314-22. |
| 24. | Singhrao SK, Harding A, Poole S, Kesavalu L, Crean S. Porphyromonas gingivalis periodontal infection and its putative links with Alzheimer’s disease. Mediators Inflamm 2015;2015:137357. |
| 25. | 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;36:665-77. |
| 26. | Lamont RJ, Hajishengallis GN, Jenkinson HF. Oral Microbiology and Immunology. Washington, DC: ASM Press 2014. p. 531. |
| 27. | Mubarokah SN, Muliartha IKG. 49.4 kda outer membrane protein of Porphyromonas gingivalis is a hemagglutinin and adhesin protein to neutrophil. Jurnal Kedokteran Brawijaya 2009;25:49-59. |
| 28. | Tribble JD, Kerr JE, Wang BY. Genetic diversity in the oral pathogen Porphyromonas gingivalis: molecular mechanisms and biological consequences. Future Microbiol 2013;8:607-20. |
| 29. | 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. |
| 30. | Dominy SS, Lynch C, Ermini F et al. Porphyromonas gingivalisin Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 2019;5:eauu3333. |
| 31. | Harding A, Robinson S, Crean S, Singhrao SK. Can better management of periodontal disease delay the onset and progression of Alzheimer’s disease? J Alzheimers Dis 2017;58:337-48. |
| 32. | Ilievski V, Zuchowska PK, Green SJ et al. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. PLoS One 2018;13:e0204941. |
| 33. | Blasko I, Grubeck-Loebenstein B. Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer’s disease. Drugs Aging 2003;20:101-13. |
| 34. | Vahabi S, Kavousinejad S, Ranjbar G, Ghasemi A, Alirezaei F. Relationship between periodontal disease and Alzheimer: a review. J Oral Hyg Health 2018;6:238. |
| 35. | Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanska L, de Leon MJ. Inflammation and Alzheimer’s disease: possible role of periodontal diseases. Alzheimers Dement 2008;4:242-50. |
[Figure 1], [Figure 2]
|
Search Pubmed for
