Microglial Cathepsin B and Porphyromonas gingivalis Gingipains as Potential Therapeutic Targets for Sporadic Alzheimer’s Disease

Author(s): Hiroshi Nakanishi*, Saori Nonaka, Zhou Wu

Journal Name: CNS & Neurological Disorders - Drug Targets
Formerly Current Drug Targets - CNS & Neurological Disorders

Volume 19 , Issue 7 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Many efforts have been made to develop therapeutic agents for Alzheimer’s Disease (AD) based on the amyloid cascade hypothesis, but there is no effective therapeutic agent at present. Now, much attention has been paid to infiltrate pathogens in the brain as a trigger of AD. These pathogens, or their virulence factors, may directly cross a weakened blood-brain barrier, reach the brain and cause neurological damage by eliciting neuroinflammation. Moreover, there is growing clinical evidence of a correlation between periodontitis and cognitive decline in AD patients. Recent studies have revealed that microglial cathepsin B is increasingly induced by lipopolysaccharide of Porphylomonas gingivalis, a major pathogen of periodontal disease. Moreover, gingipains produced by P. gingivalis play critical roles in neuroinflammation mediated by microglia and cognitive decline in mice. Furthermore, an orally bioavailable and brain-permeable inhibitor of gingipain is now being tested in AD patients. It is largely expected that clinical studies countering bacterial virulence factors may pave the way to establish the prevention and early treatment of AD.

Keywords: Alzheimer`s disease, cathepsin B, gingipain, microglia, neuroinflammation, periodontitis, Porphylomonas gingivalis.

[1]
Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol 2011; 7(3): 137-52.
[http://dx.doi.org/10.1038/nrneurol.2011.2] [PMID: 21304480]
[2]
Chakrabarti S, Khemka VK, Banerjee A, Chatterjee G, Ganguly A, Biswas A. Metabolic risk factors of sporadic Alzheimer’s disease: implications in the pathology, pathogenesis and treatment. Aging Dis 2015; 6(4): 282-99.
[http://dx.doi.org/10.14336/AD.2014.002] [PMID: 26236550]
[3]
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(4): 242-50.
[http://dx.doi.org/10.1016/j.jalz.2007.08.004] [PMID: 18631974]
[4]
Kamer AR, Dasanayake AP, Craig RG, Glodzik-Sobanska L, Bry M, de Leon MJ. Alzheimer’s disease and peripheral infections: the possible contribution from periodontal infections, model and hypothesis. J Alzheimers Dis 2008; 13(4): 437-49.
[http://dx.doi.org/10.3233/JAD-2008-13408] [PMID: 18487851]
[5]
Ide M, Harris M, Stevens A, et al. Periodontitis and cognitive decline in Alzheimer’s disease. PLoS One 2016; 11(3)e0151081
[http://dx.doi.org/10.1371/journal.pone.0151081] [PMID: 26963387]
[6]
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; 2015137357
[http://dx.doi.org/10.1155/2015/137357] [PMID: 26063967]
[7]
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(1)1563405
[http://dx.doi.org/10.1080/20002297.2018.1563405] [PMID: 30728914]
[8]
Singhrao SK, Olsen I. Are Porphyromonas gingivalis outer membrane vesicles microbullets for sporadic Alzheimer’s disease manifestation? J Alzheimers Dis Rep 2018; 2(1): 219-28.
[http://dx.doi.org/10.3233/ADR-180080] [PMID: 30599043]
[9]
Hashioka S, Inoue K, Miyaoka T, et al. The possible causal link of periodontitis to neuropsychiatric disorders: more than psychosocial mechanisms. Int J Mol Sci 2019; 20(15): 3723.
[http://dx.doi.org/10.3390/ijms20153723] [PMID: 31366073]
[10]
Cheng R, Liu W, Zhang R, Feng Y, Bhowmick NA, Hu T. Porphyromonas gingivalis-derived lipopolysaccharide combines hypoxia to induce caspase-1 activation in periodontitis. Front Cell Infect Microbiol 2017; 7: 474.
[http://dx.doi.org/10.3389/fcimb.2017.00474] [PMID: 29184853]
[11]
Imamura T. The role of gingipains in the pathogenesis of periodontal disease. J Periodontol 2003; 74(1): 111-8.
[http://dx.doi.org/10.1902/jop.2003.74.1.111] [PMID: 12593605]
[12]
Wu Z, Nakanishi H. Connection between periodontitis and Alzheimer’s disease: possible roles of microglia and leptomeningeal cells. J Pharmacol Sci 2014; 126(1): 8-13.
[http://dx.doi.org/10.1254/jphs.14R11CP] [PMID: 25168594]
[13]
Wu Z, Ni J, Liu Y, 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.
[http://dx.doi.org/10.1016/j.bbi.2017.06.002] [PMID: 28610747]
[14]
Zhang J, Yu C, Zhang X, 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.
[http://dx.doi.org/10.1186/s12974-017-1052-x] [PMID: 29426327]
[15]
Liu Y, Wu Z, Nakanishi Y, 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.
[http://dx.doi.org/10.1038/s41598-017-12173-1] [PMID: 28924232]
[16]
Dominy SS, Lynch C, Ermini F, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 2019; 5(1)eaau3333
[http://dx.doi.org/10.1126/sciadv.aau3333] [PMID: 30746447]
[17]
Gheorghita D, Eördegh G, Nagy F, Antal M. Periodontal disease, a risk factor for atherosclerotic cardiovascular disease. Orv Hetil 2019; 160(11): 419-25.
[http://dx.doi.org/10.1556/650.2019.31301] [PMID: 30852909]
[18]
Stanko P, Izakovicova Holla L. Bidirectional association between diabetes mellitus and inflammatory periodontal disease. A review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2014; 158(1): 35-8.
[http://dx.doi.org/10.5507/bp.2014.005] [PMID: 24509898]
[19]
Pischon N, Heng N, Bernimoulin JP, Kleber BM, Willich SN, Pischon T. Obesity, inflammation, and periodontal disease. J Dent Res 2007; 86(5): 400-9.
[http://dx.doi.org/10.1177/154405910708600503] [PMID: 17452558]
[20]
Noble JM, Borrell LN, Papapanou PN, Elkind MS, Scarmeas N, Wright CB. Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III. J Neurol Neurosurg Psychiatry 2009; 80(11): 1206-11.
[http://dx.doi.org/10.1136/jnnp.2009.174029] [PMID: 19419981]
[21]
Sparks Stein P, Steffen MJ, Smith C, et al. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease. Alzheimers Dement 2012; 8(3): 196-203.
[http://dx.doi.org/10.1016/j.jalz.2011.04.006] [PMID: 22546352]
[22]
Ebersole JL, Steffen MJ, Cappelli D. Longitudinal human serum antibody responses to outer membrane antigens of Actinobacillus actinomycetemcomitans. J Clin Periodontol 1999; 26(11): 732-41.
[http://dx.doi.org/10.1034/j.1600-051X.1999.t01-5-261101.x] [PMID: 10589809]
[23]
Kinane DF, Mooney J, Ebersole JL. Humoral immune response to Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in periodontal disease. Periodontol 2000; 20: 280-340.
[24]
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.
[http://dx.doi.org/10.3233/JAD-121918] [PMID: 23666172]
[25]
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(2): 113-8.
[http://dx.doi.org/10.1046/j.0902-0055.2001.00100.x] [PMID: 11929559]
[26]
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.
[http://dx.doi.org/10.1186/s13195-017-0282-6] [PMID: 28784164]
[27]
Terada K, Yamada J, Hayashi Y, et al. Involvement of cathepsin B in the processing and secretion of interleukin-1β in chromogranin A-stimulated microglia. Glia 2010; 58(1): 114-24.
[http://dx.doi.org/10.1002/glia.20906] [PMID: 19544382]
[28]
Sun L, Wu Z, Hayashi Y, et al. Microglial cathepsin B contributes to the initiation of peripheral inflammation-induced chronic pain. J Neurosci 2012; 32(33): 11330-42.
[http://dx.doi.org/10.1523/JNEUROSCI.0677-12.2012] [PMID: 22895716]
[29]
Nakanishi H. Microglial cathepsin B as a key driver of inflammatory brain diseases and brain aging. Neural Regen Res 2020; 15(1): 25-9.
[http://dx.doi.org/10.4103/1673-5374.264444] [PMID: 31535638]
[30]
Ni J, Wu Z, Peterts C, Yamamoto K, Qing H, Nakanishi H. The critical role of proteolytic relay through cathepsins B and E in the phenotypic change of microglia/macrophage. J Neurosci 2015; 35(36): 12488-501.
[http://dx.doi.org/10.1523/JNEUROSCI.1599-15.2015] [PMID: 26354916]
[31]
Ni J, Wu Z, Stoka V, et al. Increased expression and altered subcellular distribution of cathepsin B in microglia induce cognitive impairment through oxidative stress and inflammatory response in mice. Aging Cell 2019; 18(1)e12856
[http://dx.doi.org/10.1111/acel.12856] [PMID: 30575263]
[32]
Ju Hwang C, Choi DY, Park MH, Hong JT. NF-κB as a key mediator of brain inflammation in Alzheimer’s disease. CNS Neurol Disord Drug Targets 2019; 18(1): 3-10.
[http://dx.doi.org/10.2174/1871527316666170807130011] [PMID: 28782486]
[33]
Arimatsu K, Yamada H, Miyazawa H, et al. Oral pathobiont induces systemic inflammation and metabolic changes associated with alteration of gut microbiota. Sci Rep 2014; 4: 4828.
[http://dx.doi.org/10.1038/srep04828] [PMID: 24797416]
[34]
Wu Z, Nakanishi H. Lessons from microglia aging for the link between inflammatory bone disorders and Alzheimer’s disease. J Immunol Res 2015; 2015471342
[http://dx.doi.org/10.1155/2015/471342] [PMID: 26078980]
[35]
Dekita M, Wu Z, Ni J, et al. Cathepsin S is involved in Th17 differentiation through the upregulation of IL-6 by activating PAR-2 after systemic exposure to lipopolysaccharide from Porphyromonas gingivalis. Front Pharmacol 2017; 8: 470.
[http://dx.doi.org/10.3389/fphar.2017.00470] [PMID: 28769800]
[36]
Nie R, Wu Z, Ni J, et al. Porphyromonas gingivalis infection induces amyloid-beta accumulation in monocytes/macrophages. J Alzheimers Dis 2019; 72(2): 479-94.
[http://dx.doi.org/10.3233/JAD-190298] [PMID: 31594220]
[37]
Wang RP, Ho YS, Leung WK, Goto T, Chang RC. Systemic inflammation linking chronic periodontitis to cognitive decline. Brain Behav Immun 2019; 81: 63-73.
[http://dx.doi.org/10.1016/j.bbi.2019.07.002] [PMID: 31279681]
[38]
Harach T, Marungruang N, Duthilleul N, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep 2017; 7: 41802.
[http://dx.doi.org/10.1038/srep41802] [PMID: 28176819]
[39]
Erny D, Hrabě de Angelis AL, Jaitin D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci 2015; 18(7): 965-77.
[http://dx.doi.org/10.1038/nn.4030] [PMID: 26030851]
[40]
Kadowaki T, Nakayama K, Okamoto K, et al. Porphyromonas gingivalis proteinases as virulence determinants in progression of periodontal diseases. J Biochem 2000; 128(2): 153-9.
[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a022735] [PMID: 10920248]
[41]
Nakayama K. Porphyromonas gingivalis and related bacteria: from colonial pigmentation to the type IX secretion system and gliding motility. J Periodontal Res 2015; 50(1): 1-8.
[http://dx.doi.org/10.1111/jre.12255] [PMID: 25546073]
[42]
Guo Y, Nguyen KA, Potempa J. Dichotomy of gingipains action as virulence factors: from cleaving substrates with the precision of a surgeon’s knife to a meat chopper-like brutal degradation of proteins. Periodontol 2000 2010; 54(1): 15-44.
[http://dx.doi.org/10.1111/j.1600-0757.2010.00377.x] [PMID: 20712631]
[43]
Hočevar K, Potempa J, Turk B. Host cell-surface proteins as substrates of gingipains, the main proteases of Porphyromonas gingivalis. Biol Chem 2018; 399(12): 1353-61.
[http://dx.doi.org/10.1515/hsz-2018-0215] [PMID: 29927743]
[44]
Smalley JW, Olczak T. Heme acquisition mechanisms of Porphyromonas gingivalis - strategies used in a polymicrobial community in a heme-limited host environment. Mol Oral Microbiol 2017; 32(1): 1-23.
[http://dx.doi.org/10.1111/omi.12149] [PMID: 26662717]
[45]
Klarström Engström K, Khalaf H, Kälvegren H, Bengtsson T. The role of Porphyromonas gingivalis gingipains in platelet activation and innate immune modulation. Mol Oral Microbiol 2015; 30(1): 62-73.
[http://dx.doi.org/10.1111/omi.12067] [PMID: 25043711]
[46]
Shi Y, Ratnayake DB, Okamoto K, Abe N, Yamamoto K, Nakayama K. Genetic analyses of proteolysis, hemoglobin binding, and hemagglutination of Porphyromonas gingivalis. Construction of mutants with a combination of rgpA, rgpB, kgp, and hagA. J Biol Chem 1999; 274(25): 17955-60.
[http://dx.doi.org/10.1074/jbc.274.25.17955] [PMID: 10364243]
[47]
Li N, Collyer CA. Gingipains from Porphyromonas gingivalis - Complex domain structures confer diverse functions. Eur J Microbiol Immunol (Bp) 2011; 1(1): 41-58.
[http://dx.doi.org/10.1556/EuJMI.1.2011.1.7] [PMID: 24466435]
[48]
Nonaka M, Shoji M, Kadowaki T, et al. Analysis of a Lys-specific serine endopeptidase secreted via the type IX secretion system in Porphyromonas gingivalis. FEMS Microbiol Lett 2014; 354(1): 60-8.
[http://dx.doi.org/10.1111/1574-6968.12426] [PMID: 24655155]
[49]
Ramachandran R, Noorbakhsh F, Defea K, Hollenberg MD. Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov 2012; 11(1): 69-86.
[http://dx.doi.org/10.1038/nrd3615] [PMID: 22212680]
[50]
Afkhami-Goli A, Noorbakhsh F, Keller AJ, et al. Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer’s disease. J Immunol 2007; 179(8): 5493-503.
[http://dx.doi.org/10.4049/jimmunol.179.8.5493] [PMID: 17911636]
[51]
Bohm SK, Kong W, Bromme D, et al. Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J 1996; 314(Pt 3): 1009-16.
[http://dx.doi.org/10.1042/bj3141009] [PMID: 8615752]
[52]
Déry O, Thoma MS, Wong H, Grady EF, Bunnett NW. Trafficking of proteinase-activated receptor-2 and β-arrestin-1 tagged with green fluorescent protein. β-Arrestin-dependent endocytosis of a proteinase receptor. J Biol Chem 1999; 274(26): 18524-35.
[http://dx.doi.org/10.1074/jbc.274.26.18524] [PMID: 10373461]
[53]
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(10)e0204941
[http://dx.doi.org/10.1371/journal.pone.0204941] [PMID: 30281647]
[54]
Dorn BR, Dunn WA Jr, Progulske-Fox A. Porphyromonas gingivalis traffics to autophagosomes in human coronary artery endothelial cells. Infect Immun 2001; 69(9): 5698-708.
[http://dx.doi.org/10.1128/IAI.69.9.5698-5708.2001] [PMID: 11500446]
[55]
McGeer PL, McGeer EG. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol 2013; 126(4): 479-97.
[http://dx.doi.org/10.1007/s00401-013-1177-7] [PMID: 24052108]
[56]
Olmos-Alonso A, Schetters ST, Sri S, et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 2016; 139(Pt 3): 891-907.
[http://dx.doi.org/10.1093/brain/awv379] [PMID: 26747862]
[57]
Spangenberg EE, Lee RJ, Najafi AR, et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology. Brain 2016; 139(Pt 4): 1265-81.
[http://dx.doi.org/10.1093/brain/aww016] [PMID: 26921617]
[58]
Singh A, Hasan A, Tiwari S, Pandey LM. Therapeutic advancement in Alzheimer disease: New hopes on the horizon? CNS Neurol Disord Drug Targets 2018; 17(8): 571-89.
[http://dx.doi.org/10.2174/1871527317666180627122448] [PMID: 29952273]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 7
Year: 2020
Page: [495 - 502]
Pages: 8
DOI: 10.2174/1871527319666200708125130
Price: $65

Article Metrics

PDF: 36
HTML: 4