Keshava Abbayya, Nagraj Y Puthanakar,1 Sanjay Naduwinmani,2 and Y S Chidambar3

Alzheimer’s disease (AD) is a neurodegenerative disease that is more likely to develop with age. Onset can occur either early or late. AD is characterised by essential inflammatory properties, microglial activation and increased levels of pro-inflammatory cytokines that contribute to the inflammatory status of the central nervous system (CNS). Since periodontal disease is a common oral infection associated with anaerobic gram negative bacteria. Periodontal disease can be categorized as a “low-grade systemic disease” by the release of pro-inflammatory cytokines into the systemic circulation and the increase of C-Reactive Protein. Inflammation is known to play an important role in amandouan, the pathological process serving as a connector between periodontal disease and BA. This analysis is done by collecting data from the PubMed database using keywords such as “Alzheimer’s disease”, “inflammation”, “periodontal disease” and “proinflammatory cytokines”.

Keywords: “Alzheimer’s disease”, “inflammation”, “periodontal disease” and “proinflammatory cytokines”.

Introduction

Alzheimer’s disease (AD) is a fatal neurodegenerative disease associated with old age and a major health problem in the geriatric population worldwide. The incidence of AD increases significantly with age, reaching nearly 50% of subjects worldwide. [1] As population age and lifespan increase, the prevalence of BA will increase even more and is expected to affect around 14 million people in the next 50 years. A decrease in the prevalence of BA can be achieved by switching to new treatment manners that can be effective against the likely risk factors of BA and also delay treatment. [2]

The onset of BA can occur either early or late. Early onset is thought to be genetically controlled, while late or sporadic onset, which is found in most patients, appears to be the result of an interaction between genetics and environmental factors.Age is a major risk factor for BA. Other risk factors for late onset include family history, education, high fat diet, hypertension, diabetes, history of head trauma and susceptibility to genes such as apolipoprotein E (APOE). Among all these risk factors, age, head trauma and APOE are considered to be accepted risk factors. Periodontal disease is also considered a likely risk for BA. It is a chronic inflammation of the surrounding tissue of the teeth, which is due to complex bacterial interactions, resulting in loss of structure around the teeth. The present analysis elucidates the enigmatic link between BA and periodontal disease and the possible implications of the association.

BA is characterized by the formation of an extracellular plaque of amyloid peptides and masses of hyperphosphorylated intraneuronal neurofibrillary proteins (NFTs), leading to gradual loss of neuronal synapses and eventually neuronal degeneration with a decrease in essential neurotransmitters. [3] Genetic aberrations increase the expression of amyloid precursor protein (APP) genes which could be a factor in the late onset of AD. It is also likely that APOE epsilon 4 alleles are genetically linked to most cases of BA. [4]

Pathogenesis of Alzheimer’s disease

BA tends to induce inflammation, including A-amyloid 1-42 peptide (A42) found in senile plaque, tau hyperphosphorylated protein (P-Tau) comprising NFTs or components of degenerative neurons. [3] Instead, these pathological changes are likely to stimulate microglial cells. these protective microglial cells at low levels of concentration. They help maintain homeostasis in the brain by functioning as a mononuclear phagocyte against any harmful damage in the central nervous system (CNS). In healthy individuals, microglial cells play a neuroprotective role by clearing AP plaques.[5] With advancing age and genetic predisposition, the normal neuroprotective capacity of microglial cells is compromised, resulting in the persistence of a chronic inflammatory response in the CNS.6,7] This causes brain microglial cells, by their phenotype, to produce neurotoxic substances when exposed to systemic inflammatory signals. Such a microglial cell response contributes to the pathogenesis of BA, rather than providing a protective response to systemic inflammatory signals. Induced microglial cells, now called “activated microglial cells”, alter their morphology and secrete antigenic cells, which in turn result in uncontrolled expression of proinflammatory factors. This uncontrolled expression of factor levels, as in BA, may induce neurodegeneration, suggesting that expression of inflammatory mu muculoeukles will contribute to the progression of BA[8].

Microglial cells in Alzheimer’s disease

The function of the microglial cell is like a “double-edged sword”, being either destructive or protective depending on the situation. [9,10,11] Activated/stimulated microglial cells produce proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6 and C-reactive protein (CRP). Proinflammatory cytokines and CRP could then act via paracrine and/or autocrine pathways to stimulate glial cells and activate molecular pathways, resulting in neurodegeneration.[12] Senile plaques are associated with reactive astrocytes and activate microglial cells that react with antibodies against TNF, IL-1, IL-6, CRP and complement preoteins.TNF, IL-1, IL-6 are capable of stimulating synthesis of A42 and phosphorylated tau protein and A42 and P-Tau can stimulate production of TNF, IL-1, and IL-6 by glial cells[12,13,14].

Research studies have revealed the correlation between CRP value and other systemic inflammatory markers in the onset of BA. Increased CRP levels increase the risk of developing BA in diverse populations.[15,16] A case-control study of 1050 subjects reported that increased CRP levels increase the risk of developing BA 25 years later.[17,18] The presence of a composite genotype characterized by the presence of IL-1-889 IL-1 + 3953 polymorphic confers almost 11-fold risk of developing BA, probably due to increased IL-1 levels.

Mechanisms involved in the spread of inflammation to the brain

There are two mechanisms involved in the brain that cause proinflammatory molecules to increase, these are, via systemic circulation and/or neural pathways. In the systemic circulation, proinflammatory molecules enter the brain through areas lacking a blood-brain barrier. Alternatively, these inflammatory molecules can also enter the blood-brain barrier sites in the brain via:

(a) Fenestrated capillaries of the blood-brain barrier,

(b) Using specific cytokine transporters,

(c) Increasing the permeability of the blood-brain barrier or

(d) Brain endothelial cells are activated to produce signaling molecules for the induction of cytokines such as nitric oxide.

As pro-inflammatory molecules enter the brain, there is an increase in pro-inflammatory cytokines or a stimulation of glial cells to synthesize additional pro-inflammatory cytokines. An alternative pathway by which cytokines derived from peripheral inflammatory sources may affect the brain is via the neuronal pathway[20] Peripheral cytokines have the ability to stimulate afferent fibers of peripheral nerves, resulting in increased levels of cytokines in the brain; similarly, they may also use channels or compartments associated with peripheral nerves to enter the brain.

Another mechanism includes the presence of receptors for CD14 present in the brain that can be activated by LPS derived from invasive bacteria or AD AP, which in turn will activate CD14 cells. These CD14 cells are exposed to systemic circulations such as the leptomeninges, circumventricular areas and choroid plexus; therefore, they further increase cytokines in the brain and hypothetically contribute to the BA inflammatory burden.

Microbiota in Alzheimer’s disease

The role of bacteria, in pathogenesis, BA is known to be given by Chlamydia Pneumoniae and Spirochaetes which is highlighted in some studies conducted. The presence of Borrelia Burgdorferi spirochetes was found in the blood and cerebrospinal fluid of patients with BA and it was also observed that glial and neuronal cells exposed to Borrelia Burgdorferi synthesized APP and P-TAUS. [21]

Spirochetes and Treponema denticola are commonly isolated microorganisms in moderate and severe periodontal disease[22].These organisms are also detected in patients with BA suggesting that periodontal bacteria can invade the brain via the systemic circulation as well as the peripheral nerve pathways. Invasion of microorganisms through the neural pathways is supported by the presence of oral treponemes in the trigeminal ganglion.23,24] The presence of oral bacteria in the systemic circulation is usually expected when bacterial plaque is present in large amounts. AP, the major component of amyloid plaque is derived from APP by proteolytic cleavage. Studies support the hypothesis that APP and AP are instrumental in the pathogenesis of BA[25].

The stability of microtubules in neurons is maintained by the associated tau protein. But tau hyperphosphorylation occurs as a result of inflammation, oxidative stress, overregulation of tau kinase.This tau hyperphosphorylation is insoluble with low affinity for the microtubule, breaking microtubule stability, therefore leading to synaptic dysfunction and neurodegeneration.

BA was thought to be a disease related to the synthesis and decaying decline of PA. But with the introduction of the “amyloid cascade hypothesis”, impaired PA clearance is also established as a cofactor with APP playing a crucial role[27].

Studies have shown that chronic lipopolysaccharide-induced neuroinflammation results in increased levels of intranuronal PA in transgenic mice. This may contribute to damage of the affected brain in BA [28,29,30].

Periodontal Disease: As a systemic disease of a low grade

Periodontal disease (PD) is a condition that causes inflammation and destruction of the gums, alveolar bone and other structures supporting the tooth. The aetiology of BP is complex, involving the presence of pathogenic bacteria found in dental plaque triggering the immune system response. BP is a common source of chronic systemic inflammation and immune reaction resulting in the loss of bone and soft tissue supporting the teeth in the jaws[31].

BA is mostly the result of an existing plaque in the constitution of the biofilm and is composed of numerous microorganisms. Periodontal disease features include bleeding and pus from the gums, evolving gingival sulcus (formation of periodontal pockets), oral halitosis, spaces between teeth and tooth mobility in advanced stages. The most common periodontal pathogens involved in BP are: Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Fusobacterium nucleatum (Fn), Tannerella forsythensis (Tf), Eikenella corrodens (Ec), and Treponema denticola (Td)[32,33].

The inflammatory process in BP extends from the gum to deeper tissues, resulting in loss of connective tissue and bone, mainly through activation of derived odteoclasts and matrix metalloproteinases (MMPs). The connective tissue adjacent to the epithelial pouch is infiltrated with inflammatory cells such as polymorphonuclear leukocytes, monocytes/macrophages, B and T cells mediated by a multitude of cytokines and mostly produced by the inflammatory cells themselves[34].This low degree of inflammation is designed to disrupt general systemic health and aggravates other systemic disorders. Therefore, chronic periodontal disease may be a significant source of peripheral inflammation in the general population[35] Therefore, BP can be classified as a “low-grade systemic disease”.

BP is actually a result of inflammation caused by the widespread distribution of pathogenic microorganisms [Fig 1] These microorganisms release numerous proteolytic enzymes, resulting in the destruction of the soft and hard tissue that supports the tooth. The release of LPS from gram-negative bacteria results in the expression of proinflammatory factors and cytokines such as IL-1, -1, IL-6, TNF, prostanoids, MMP and host tissue cells (neutrophils and monocytes); ultimately leading to further destruction of periodontal tissue. Thus, the host response plays a diabolical “dual role” role, leading to self-destruction due to over-expression of proteolytic enzymes[36].

Systemic effects of periodontal disease

• Periodontal bacteria and their products may be aspirated, which could induce lung pathology.
• Periodontal pathogens have the ability to gain access into the systemic circulation and subsequently colonize different anatomical sites in the body. For example, periodontal bacteria have been implicated in several systemic disorders including endocarditis and neurological abscesses.
• Periodontal bacteria and their products can disseminate into the systemic circulation in pregnant women, inducing inflammatory changes and resulting in premature low birth weight.
• Chronic adult BP has been associated with severe disorders including an increased risk of atherosclerotic complications, stroke, myocardial, poorly controlled diabetes and possibly with BA[37].
• The host immune response also plays a vital role in inducing the systemic effect by producing numerous inflammatory mediators including cytokines (against periodontal microbiota) that gain access into the systemic circulation.

The isolation of periodontal microbiota from various samples obtained from the respiratory tract, atheromatous plaque in the heart, brain, vaginal secretions and also from patients suffering from rheumatoid arthritis reveals a possible association of BP with systemic disorders.

Correlation between Alzheimer’s disease and periodontal disease

Inflammation is known to play an important role in this process. It is proposed that periodontal disease may lead to progression of BA by two possible mechanisms.

Two mechanisms have been put forward to explain the association between periodontal disease and BA

1. According to the first mechanism, the microorganisms in the BP and the host response cause an increase in pro-inflammatory cytokine levels. This results in a plethora of cytokines and proinflammatory agents being elevated in the circulatory system, leading to a burdening of the inflammatory system towards a condition of peripheral inflammation. These proinflammatory molecules are able to compromise the BBB and enter the brain regions. This leads to activation of microglial cells and adverse repercussions, causing neuronal damage.
2. The second mechanism is known to be due to invasion of the brain by microorganisms present in dental plaque biofilm. Microorganisms in dental plaque can enter the brain either through the blood circulation or through peripheral nerves. These microorganisms and their products cause an inflammatory mechanism within the CNS. It is generally accepted with appreciable evidence that the presence of inflammation in the CNS results in cognitive tubers such as those seen in BA. These inflammatory disorders are attributed to cytokines that mediate interactions between neurons and glial cells. Cytokines released due to inflammation include the IL family, TNF, growth factor and chemokines which have also been implicated as plasma and serum markers in the pathogenesis of BA.[38] Cytokines that are released during inflammation play a major role in neurodegenerative diseases. TNF intensifies the inflammatory process resulting in gliosis, demyelination, BBB damage and cell death. Therefore, TNF plays a very important role in the neurodegenerative process.39,40] Anti-inflammatory agents reduce the effect of these cytokines and other pro-inflammatory molecules during any inflammatory condition. Studies in mice have shown beneficial effects of anti-inflammatory agents in relieving neuroinflammation and amyloid plaque deposits. In addition, there is also a significant reduction in IL-1 levels and glial fibrillary acidic protein levels in mice treated with nonsteroidal anti-inflammatory agents [41,42]The role of anti-inflammatory agents has been studied by the Alzheimer’s disease Anti-inflammatory Prevention Trial (ADAPT) and it has been hypothesized that the beneficial effect of anti-inflammatory drugs is evident only in the early, asymptomatic phases of the disease. In individuals with BA elevations in IL-1 predicted a rate of cognitive decline[43] Patients with elevated markers preceding baseline levels showed a higher rate of cognitive decline over the second month of the follow-up period than those who did not have previously elevated levels. Similarly, dementia is also thought to be a complex disorder associated with an interaction between genetics and systemic inflammation-related diseases. Elevated levels of inflammatory markers in the blood predict a risk of dementia and incidence of cognitive disorders. Cross-sectional and longitudinal studies have shown that dementia occurs in subjects with poor oral hygiene. Therefore, periodontal disease leading to the presence of inflammatory molecules in the systemic circulation is considered to be a risk factor in developing a variety of systemic diseases such as BA[42].

 Conclusions

Inflammation can serve as a link between periodontal disease and BA. However, in the literature, there are no animal studies specifically addressing the causal relationship of periodontal inflammation with BA. Since periodontal disease tends to infiltrate the systemic circulation with inflammatory mediators and results in systonic disease; therefore, it is always advisable and a better option to prevent progression of periodontal disease to prevent future systemic disease.

 Bibliography

1. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Alzheimer’s Disease International. Global prevalence of dementia: A Delphi consensus study. Lancet. 2005;366:2112 7. [PMC free article] [PubMed]

Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanskad L, de Leon MJ. Inflammation and Alzheimer’s disease: Possible role of periodontal diseases. Alzheimers Dement. 2008;4:242 50. [PubMed]

3. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21:383 421.[PMC free article][PubMed]

4. Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer’s disease: Back to the future. Neuron. 2010;68:270 81.[PubMed]

5. Fetler L, Amigorena S. Neuroscience. Brain under surveillance: The microglia patrol. Science. 2005;309:392 3.[PubMed]

6. Schram MT, Euser SM, de Craen AJ, Witteman JC, Frolich M, Hofman A, et al. Systemic markers of inflammation and cognitive decline in old age. J Am Geriatr Soc. 2007;55:708 16.[PubMed]

7. Arosio B, Trabattoni D, Galimberti L, Bucciarelli P, Fasano F, Calabresi C, et al. Interleukin-10 and interleukin-6 gene polymorphisms as risk factors for Alzheimer’s disease. Neurobiol Aging. 2004;25:1009 15.[PubMed]

8. von Bernhardi R, Eugenin J. Microglial reactivity to beta-amyloid is modulated by astrocytes and proinflammatory factors. Brain Res. 2004;1025:186 93.[PubMed]

Weitz TM, Town T. Microglia in Alzheimer’s disease: It’s all about context. Int J Alzheimers Dis. 2012;2012:314185.[PMC free article][PubMed]

10. Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7:161 7.[PubMed]

11. Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci. 2005;25:8843 53.[PubMed]

12. McGeer PL, McGeer EG. Inflammation, autotoxicity and Alzheimer’s disease. Neurobiol Aging. 2001;22:799 809[PubMed].

13. Konsman JP, Drukarch B, Van Dam AM. (Peri) vascular production and action of pro-inflammatory cytokines in brain pathology. Clin Sci (Lond) 2007;112:1 25.[PubMed]

14. Gosselin D, Rivest S. Role of IL-1 and TNF in the brain: Twenty years of progress on a Dr. Jekyll/Mr Hyde duality of the innate immune system. Brain Behav Immun. 2007;21:281 9.[PubMed]

15. Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, et al. Inflammatory proteins in plasma and the risk of dementia: The rotterdam study. Arch Neurol. 2004;61:668 72.[PubMed]

16. Yaffe K, Kanaya A, Lindquist K, Simonsick EM, Harris T, Shorr RI, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA. 2004;292:2237 42.[PubMed]

17. Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation and dementia: A 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol. 2002;52:168 74.[PubMed]

Kalman J, Juhasz A, Laird G, Dickens P, Jardanhazy T, Rimanczy A, et al. Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer’s disease. Acta Neurol Scand. 1997;96:236 40.[PubMed]

19. Nicoll JA, Mrak RE, Graham DI, Stewart J, Wilcock G, MacGowan S, et al. Association of interleukin-1 gene polymorphisms with Alzheimer’s disease. Ann Neurol. 2000;47:365 8.[PMC free article][PubMed]

20. Dantzer R, Konsman JP, Bluthe RM, Kelley KW. Neural and humoral pathways of communication from the immune system to the brain: Parallel or convergent Auton Neurosci. 2000;85:605.[PubMed]

21. Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, et al. Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging. 2006;27:22836.[PubMed]

22. Ellen RP, Galimanas VB. Spirochetes at the forefront of periodontal infections. Periodontol 2000. 2005;38:1332. [PubMed]

23. Riviere GR, Riviere KH, Smith KS. Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer’s disease. Oral Microbiol Immunol. 2002;17:1138.[PubMed]

24. Foschi F, Izard J, Sasaki H, Sambri V, Prati C, Muller R, et al. Treponema denticola in disseminating endodontic infections. J Dent Res. 2006;85:7615.[PMC free article][PubMed]

25. Galimberti D, Scarpini E. Progress in Alzheimer’s disease. J Neurol. 2012;259:20111.[PubMed]

26. Lee YJ, Han SB, Nam SY, Oh KW, Hong JT. Inflammation and Alzheimer’s disease. Arch Pharm Res. 2010;33:153956. [PubMed]

27. Claeysen S, Cochet M, Donneger R, Dumuis A, Bockaert J, Giannoni P. Alzheimer culprits: Cellular crossroads and interplay. Cell Signal. 2012;24:183140.[PubMed]

28. Miller AJ, Luheshi GN, Rothwell NJ, Hopkins SJ. Local cytokine induction by LPS in the rat air pouch and its relationship to the febrile response. Am J Physiol. 1997;272:R85761.[PubMed]

29. Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation. 2008;5:37.[PMC free article][PubMed]

30. Tan ZS, Seshadri S. Inflammation in the Alzheimer’s disease cascade: Culprit or innocent bystander Alzheimers Res Ther. 2010;2:6.[PMC free article][PubMed]

31. Garcia RI, Henshaw MM, Krall EA. Relationship between periodontal disease and systemic health. Periodontol 2000. 2001;25:2136.[PubMed]

32. Socransky SS, Haffajee AD. Periodontal microbial ecology. Periodontol 2000. 2005;38:13587.[PubMed]

33. Filoche S, Wong L, Sissons CH. Oral biofilms: Emerging concepts in microbial ecology. J Dent Res. 2010;89:818. [PubMed]

34. Taubman MA, Valverde P, Han X, Kawai T. Immune response: The key to bone resorption in periodontal disease. J Periodontol. 2005;76:203341.[PubMed]

35. D’Aiuto F, Graziani F, Tet S, Gabriele M, Tonetti MS. Periodontitis: From local infection to systemic diseases. Int J Immunopathol Pharmacol. 2005;18:111.[PubMed]

36. Preshaw PM, Taylor JJ. How has research into cytokine interactions and their role in driving immune responses impacted our understanding of periodontitis J Clin Periodontol. 2011;38:6084.[PubMed]

37. 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;2:1107. [PubMed]

38. Lee KS, Chung JH, Choi TK, Suh SY, Oh BH, Hong CH. Peripheral cytokines and chemokines in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2009;28:2817. [PubMed]

39. Park KM, Bowers WJ. tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction.Cell Signal. 2010;22:97783.[PMC free article][PubMed]

40. Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol. 2012;7:4259.[PubMed]

41. Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, et al. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer’s disease. J Neurosci. 2003;23:75049.[PubMed]

42. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Kuiperi C, et al. Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain. 2005;128:144253.[PubMed]

43. Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, Perry VH. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2003;74:7889.[PMC free article][PubMed]