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首页 > 过刊浏览>2024年第51卷第11期 >4359-4369. DOI:10.13344/j.microbiol.china.240148
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牙龈卟啉单胞菌与阿尔茨海默病相关性致病机制
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首批重庆医科大学重大科技创新项目(2023[157]);重庆市自然科学基金创新发展联合基金A类项目(CSTB2022NSCQ-LZX0039);重庆医科大学青年创新科研团队(W0060)


Association of Porphyromonas gingivalis with Alzheimer’s disease
Author:
  • REN Huan

    REN Huan

    Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China;Chongqing Key Laboratory of Oral Diseases, Chongqing 401147, China;Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
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  • QIAO Xin

    QIAO Xin

    Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China;Chongqing Key Laboratory of Oral Diseases, Chongqing 401147, China;Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
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  • WANG Zheng

    WANG Zheng

    Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China;Chongqing Key Laboratory of Oral Diseases, Chongqing 401147, China;Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
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  • YANG Deqin

    YANG Deqin

    Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, China;Chongqing Key Laboratory of Oral Diseases, Chongqing 401147, China;Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, China
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  • 摘要
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    摘要:

    牙龈卟啉单胞菌(Porphyromonas gingivalis)作为牙周炎的关键致病细菌之一，与阿尔茨海默病(Alzheimer’s disease, AD)的发生发展密切相关。P.gingivalis通过分泌多种毒力因子，如脂多糖、牙龈蛋白酶及外膜囊泡，促进了AD的发展。这些毒力因子能够引发机体的炎症反应、β-淀粉样蛋白的沉积、Tau蛋白磷酸化、神经毒性作用及血脑屏障(blood brain barrier, BBB)的损害，在AD的发病机制中有重要作用。因此本文综述了P.gingivalis与AD之间的潜在致病机制，以便为AD的预防和治疗提供新的靶点。

    Abstract:

    As one of the key pathogenic bacteria of periodontitis, Porphyromonas gingivalis is closely associated with the occurrence and development of Alzheimer’s disease (AD). P. gingivalis promotes the development of AD by secreting various virulence factors, such as lipopolysaccharides (LPS), gingipains, and outer membrane vesicles (OMVs). These virulence factors are capable of inducing systemic inflammation, β-amyloid (Aβ) deposition, Tau protein phosphorylation, neurotoxicity, and damage to the blood-brain barrier (BBB), playing a role in the pathogenesis of AD. This review summarizes the association between P. gingivalis and AD, aiming to provide a new target for the prevention and treatment of AD.

    参考文献
    [1] JUNGBAUER G, STÄHLI A, ZHU XL, AUBER ALBERI L, SCULEAN A, EICK S. Periodontal microorganisms and Alzheimer disease: a causative relationship?[J]. Periodontology 2000, 2022, 89(1): 59-82.
    [2] JIA JP, WEI CB, CHEN SQ, LI FY, TANG Y, QIN W, ZHAO LN, JIN HM, XU H, WANG F, ZHOU AH, ZUO XM, WU LY, HAN Y, HAN Y, HUANG LY, WANG Q, LI D, CHU CB, SHI L, et al. The cost of Alzheimer’s disease in China and re-estimation of costs worldwide[J]. Alzheimer’s & Dementia, 2018, 14(4): 483-491.
    [3] SADRAMELI M, BATHINI P, ALBERI L. Linking mechanisms of periodontitis to Alzheimer’s disease[J]. Current Opinion in Neurology, 2020, 33(2): 230-238.
    [4] MERCHANT AT, ZHAO LG, BAWA EM, YI FL, VIDANAPATHIRANA NP, LOHMAN M, ZHANG JJ. Association between clusters of antibodies against periodontal microorganisms and Alzheimer disease mortality: evidence from a nationally representative survey in the USA[J]. Journal of Periodontology, 2024, 95(1): 84-90.
    [5] OLSEN I. Possible effects of Porphyromonas gingivalis on the blood-brain barrier in Alzheimer’s disease[J]. Expert Review of Anti-Infective Therapy, 2021, 19(11): 1367-1371.
    [6] MEI F, XIE MR, HUANG XF, LONG YL, LU XF, WANG XL, CHEN LL. Porphyromonas gingivalis and its systemic impact: current status[J]. Pathogens, 2020, 9(11): 944.
    [7] 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]. Journal of Alzheimer’s Disease, 2013, 36(4): 665-677.
    [8] STEIN PS, STEFFEN MJ, SMITH C, JICHA G, EBERSOLE JL, ABNER E, DAWSON 3rd D. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease[J]. Alzheimer’s & Dementia, 2012, 8(3): 196-203.
    [9] BAHAR B, KANAGASINGAM S, TAMBUWALA MM, ALJABALI AAA, DILLON SA, DOAEI S, WELBURY R, CHUKKAPALLI SS, SINGHRAO SK. Porphyromonas gingivalis (W83) infection induces Alzheimer’s disease-like pathophysiology in obese and diabetic mice[J]. Journal of Alzheimer’s Disease, 2021, 82(3): 1259-1275.
    [10] GABARRINI G, GRASSO S, van WINKELHOFF AJ, van DIJL JM. Gingimaps: protein localization in the oral pathogen Porphyromonas gingivalis[J]. Microbiology and Molecular Biology Reviews, 2020, 84(1): e00032-19.
    [11] GUO HY, LI B, YAO HT, LIU DF, CHEN RR, ZHOU SH, JI YT, ZENG L, DU MQ. Profiling the oral microbiomes in patients with Alzheimer’s disease[J]. Oral Diseases, 2023, 29(3): 1341-1355.
    [12] LEBLHUBER F, HUEMER J, STEINER K, GOSTNER JM, FUCHS D. Knock-on effect of periodontitis to the pathogenesis of Alzheimer’s disease?[J]. Wiener Klinische Wochenschrift, 2020, 132(17): 493-498.
    [13] CIRSTEA MS, KLIGER D, MacLELLAN AD, YU AC, LANGLOIS J, FAN MN, BOROOMAND S, KHARAZYAN F, HSIUNG RGY, MacVICAR BA, CHERTKOW H, WHITEHEAD V, FINLAY BB, APPEL-CRESSWELL S. The oral and fecal microbiota in a Canadian cohort of Alzheimer’s disease[J]. Journal of Alzheimer’s Disease, 2022, 87(1): 247-258.
    [14] TAKEUCHI K, FURUTA M, TAKESHITA T, SHIBATA Y, SHIMAZAKI Y, AKIFUSA S, NINOMIYA T, KIYOHARA Y, YAMASHITA Y. Serum antibody to Porphyromonas gingivalis and periodontitis progression: the hisayama study[J]. Journal of Clinical Periodontology, 2015, 42(8): 719-725.
    [15] NOBLE JM, BORRELL LN, PAPAPANOU PN, ELKIND MSV, SCARMEAS N, WRIGHT CB. Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III[J]. Journal of Neurology, Neurosurgery, and Psychiatry, 2009, 80(11): 1206-1211.
    [16] CHEN CK, WU YT, CHANG YC. Association between chronic periodontitis and the risk of Alzheimer’s disease: a retrospective, population-based, matched- cohort study[J]. Alzheimer’s Research & Therapy, 2017, 9(1): 56.
    [17] DOMINY SS, LYNCH C, ERMINI F, BENEDYK M, MARCZYK A, KONRADI A, NGUYEN M, HADITSCH U, RAHA D, GRIFFIN C, HOLSINGER LJ, ARASTU-KAPUR S, KABA S, LEE A, RYDER MI, POTEMPA B, MYDEL P, HELLVARD A, ADAMOWICZ K, HASTURK H, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors[J]. Science Advances, 2019, 5(1): eaau3333.
    [18] HAYASHI K, HASEGAWA Y, TAKEMOTO Y, CAO C, TAKEYA H, KOMOHARA Y, MUKASA A, KIM- MITSUYAMA S. Continuous intracerebroventricular injection of Porphyromonas gingivalis lipopolysaccharide induces systemic organ dysfunction in a mouse model of Alzheimer’s disease[J]. Experimental Gerontology, 2019, 120: 1-5.
    [19] GU YB, WU Z, ZENG F, JIANG MZ, TEELING JL, NI JJ, TAKAHASHI I. Systemic exposure to lipopolysaccharide from Porphyromonas gingivalis induces bone loss-correlated Alzheimer’s disease-like pathologies in middle-aged mice[J]. Journal of Alzheimer’s Disease, 2020, 78(1): 61-74.
    [20] JIANG MZ, ZHANG XW, YAN X, MIZUTANI S, KASHIWAZAKI H, NI JJ, WU Z. GSK3β is involved in promoting Alzheimer’s disease pathologies following chronic systemic exposure to Porphyromonas gingivalis lipopolysaccharide in amyloid precursor protein NL-F/NL-F knock-in mice[J]. Brain, Behavior, and Immunity, 2021, 98: 1-12.
    [21] QIAN XS, ZHANG S, DUAN L, YANG FC, ZHANG K, YAN FH, GE S. Periodontitis deteriorates cognitive function and impairs neurons and Glia in a mouse model of Alzheimer’s disease[J]. Journal of Alzheimer’s Disease, 2021, 79(4): 1785-1800.
    [22] DING Y, REN JY, YU HQ, YU WX, ZHOU YM. Porphyromonas gingivalis, a periodontitis causing bacterium, induces memory impairment and age-dependent neuroinflammation in mice[J]. Immunity & Ageing: I&A, 2018, 15: 6.
    [23] FU YW, XU X, ZHANG Y, YUE P, FAN YX, LIU MX, CHEN JJ, LIU AH, ZHANG XF, BAO FK. Oral Porphyromonas gingivalis infections increase the risk of Alzheimer’s disease: a review[J]. Oral Health & Preventive Dentistry, 2023, 21: 7-16.
    [24] LEE HJ, HOE HS. Inhibition of CDK4/6 regulates AD pathology, neuroinflammation and cognitive function through DYRK1A/STAT3 signaling[J]. Pharmacological Research, 2023, 190: 106725.
    [25] ZHANG ZY, LIU DJ, LIU S, ZHANG SW, PAN YP. The role of Porphyromonas gingivalis outer membrane vesicles in periodontal disease and related systemic diseases[J]. Frontiers in Cellular and Infection Microbiology, 2021, 10: 585917.
    [26] GONG T, CHEN Q, MAO HC, ZHANG Y, REN H, XU MM, CHEN H, YANG DQ. Outer membrane vesicles of Porphyromonas gingivalis trigger NLRP3 inflammasome and induce neuroinflammation, tau phosphorylation, and memory dysfunction in mice[J]. Frontiers in Cellular and Infection Microbiology, 2022, 12: 925435.
    [27] WEI SC, PENG WJ, MAI YR, LI KL, WEI W, HU L, ZHU SP, ZHOU HH, JIE WX, WEI ZS, KANG CY, LI RK, LIU Z, ZHAO B, CAI ZY. Outer membrane vesicles enhance tau phosphorylation and contribute to cognitive impairment[J]. Journal of Cellular Physiology, 2020, 235(5): 4843-4855.
    [28] OWOYELE PV, MALEKZADEH S. Porphyromonas gingivalis, neuroinflammation and Alzheimer’s disease[J]. Nigerian Journal of Physiological Sciences: Official Publication of the Physiological Society of Nigeria, 2022, 37(2): 157-164.
    [29] LENG FD, EDISON P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?[J]. Nature Reviews Neurology, 2021, 17: 157-172.
    [30] JOSHI DC, ZHANG CL, MATHUR D, LI A, KAUSHIK G, SHENG ZH, CHIU SY. Tripartite crosstalk between cytokine IL-1β, NMDA-R and misplaced mitochondrial anchor in neuronal dendrites is a novel pathway for neurodegeneration in inflammatory diseases[J]. The Journal of Neuroscience, 2022, 42(38): 7318-7329.
    [31] AL-GHRAIYBAH NF, WANG JW, ALKHALIFA AE, ROBERTS AB, RAJ R, YANG E, KADDOUMI A. Glial cell-mediated neuroinflammation in Alzheimer’s disease[J]. International Journal of Molecular Sciences, 2022, 23(18): 10572.
    [32] ZHANG J, YU CB, ZHANG X, CHEN HW, DONG JC, LU WL, SONG ZC, ZHOU W. Porphyromonas gingivalis lipopolysaccharide induces cognitive dysfunction, mediated by neuronal inflammation via activation of the TLR4 signaling pathway in C57BL/6 mice[J]. Journal of Neuroinflammation, 2018, 15(1): 37.
    [33] HU Y, LI HX, ZHANG J, ZHANG X, XIA XY, QIU C, LIAO Y, CHEN HW, SONG ZC, ZHOU W. Periodontitis induced by P. gingivalis-LPS is associated with neuroinflammation and learning and memory impairment in sprague-dawley rats[J]. Frontiers in Neuroscience, 2020, 14: 658.
    [34] NAKANISHI H, NONAKA S, WU Z. Microglial cathepsin B and Porphyromonas gingivalis gingipains as potential therapeutic targets for sporadic Alzheimer’s disease[J]. CNS & Neurological Disorders Drug Targets, 2020, 19(7): 495-502.
    [35] MEMEDOVSKI Z, CZERWONKA E, HAN J, MAYER J, LUCE M, KLEMM LC, HALL ML, MAYER AMS. Classical and alternative activation of rat microglia treated with ultrapure Porphyromonas gingivalis lipopolysaccharide in vitro[J]. Toxins, 2020, 12(5): 333.
    [36] NIE R, WU Z, NI JJ, ZENG F, YU WX, ZHANG YF, KADOWAKI T, KASHIWAZAKI H, TEELING JL, ZHOU YM. Porphyromonas gingivalis infection induces amyloid-β accumulation in monocytes/ macrophages[J]. Journal of Alzheimer’s Disease, 2019, 72(2): 479-494.
    [37] LEIRA Y, IGLESIAS-REY R, GÓMEZ-LADO N, AGUIAR P, CAMPOS F, D’AIUTO F, CASTILLO J, BLANCO J, SOBRINO T. Porphyromonas gingivalis lipopolysaccharide-induced periodontitis and serum amyloid-beta peptides[J]. Archives of Oral Biology, 2019, 99: 120-125.
    [38] REYES L. Porphyromonas gingivalis[J]. Trends in Microbiology, 2021, 29(4): 376-377.
    [39] HADITSCH U, ROTH T, RODRIGUEZ L, HANCOCK S, CECERE T, NGUYEN M, ARASTU-KAPUR S, BROCE S, RAHA D, LYNCH CC, HOLSINGER LJ, DOMINY SS, ERMINI F. Alzheimer’s disease-like neurodegeneration in Porphyromonas gingivalis infected neurons with persistent expression of active gingipains[J]. Journal of Alzheimer’s Disease, 2020, 75(4): 1361-1376.
    [40] GROBLER C, van TONGEREN M, GETTEMANS J, KELL DB, PRETORIUS E. Alzheimer’s disease: a systems view provides a unifying explanation of its development[J]. Journal of Alzheimer’s Disease, 2023, 91(1): 43-70.
    [41] CHU J, LAURETTI E, PRATICÒ D. Caspase-3- dependent cleavage of Akt modulates tau phosphorylation via GSK3β kinase: implications for Alzheimer’s disease[J]. Molecular Psychiatry, 2017, 22(7): 1002-1008.
    [42] OLSEN I, SINGHRAO SK. Is there a link between genetic defects in the complement cascade and Porphyromonas gingivalis in Alzheimer’s disease?[J]. Journal of Oral Microbiology, 2019, 12(1): 1676486.
    [43] VEITH PD, GLEW MD, GORASIA DG, CASCALES E, REYNOLDS EC. The type IX secretion system and its role in bacterial function and pathogenesis[J]. Journal of Dental Research, 2022, 101(4): 374-383.
    [44] 刘忠斌, 龙伟, 黄嘉玲, 徐依萍, 葛颂. 牙龈卟啉单胞菌外膜囊泡与阿尔茨海默病的相关性研究进展[J]. 微生物学通报, 2023, 50(8): 3647-3658. LIU ZB, LONG W, HUANG JL, XU YP, GE S. Relationship between Porphyromonas gingivalis outer membrane vesicles and Alzheimer’s disease: a review[J]. Microbiology China, 2023, 50(8): 3647-3658(in Chinese).
    [45] KIM JY, SUH JW, KANG JS, KIM SB, YOON YK, SOHN JW. Gram-negative bacteria’s outer membrane vesicles[J]. Infection & Chemotherapy, 2023, 55(1): 1-9.
    [46] NARA PL, SINDELAR D, PENN MS, POTEMPA J. Porphyromonas gingivalis outer membrane vesicles as the major driver of and explanation for neuropathogenesis, the cholinergic hypothesis, iron dyshomeostasis, and salivary lactoferrin in Alzheimer’s disease[J]. Journal of Alzheimer’s Disease, 2021, 82(4): 1417-1450.
    [47] HAN EC, CHOI SY, LEE Y, PARK JW, HONG SH, LEE HJ. Extracellular RNAs in periodontopathogenic outer membrane vesicles promote TNF-α production in human macrophages and cross the blood-brain barrier in mice[J]. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 2019, 33(12): 13412-13422.
    [48] LEE KE, KIM JK, HAN SK, LEE DY, LEE HJ, YIM SV, KIM DH. The extracellular vesicle of gut microbial Paenalcaligenes hominis is a risk factor for vagus nerve-mediated cognitive impairment[J]. Microbiome, 2020, 8(1): 107.
    [49] 温娜娜, 郑国华. 肠道菌群与老年认知障碍的研究进展[J]. 微生物学通报, 2023, 50(2): 697-708. WEN NN, ZHENG GH. Research progress on gut microbiota and cognitive impairment in the elderly[J]. Microbiology China, 2023, 50(2): 697-708(in Chinese).
    [50] CHEN XW, SUN GQ, TIAN E, ZHANG MZ, DAVTYAN H, BEACH TG, REIMAN EM, BLURTON-JONES M, HOLTZMAN DM, SHI YH. Modeling sporadic Alzheimer’s disease in human brain organoids under serum exposure[J]. Advanced Science, 2021, 8(18): e2101462.
    [51] KURZ C, WALKER L, RAUCHMANN BS, PERNECZKY R. Dysfunction of the blood-brain barrier in Alzheimer’s disease: evidence from human studies[J]. Neuropathology and Applied Neurobiology, 2022, 48(3): e12782.
    [52] TSARTSALIS S, SLEVEN H, FANCY N, WESSELY F, SMITH AM, WILLUMSEN N, CHEUNG TKD, ROKICKI MJ, CHAU V, IFIE E, KHOZOIE C, ANSORGE O, YANG X, JENKYNS MH, DAVEY K, McGARRY A, MUIRHEAD RCJ, DEBETTE S, JACKSON JS, MONTAGNE A, et al. A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease[J]. Nature Communications, 2024, 15: 2243.
    [53] FARRUGIA C, STAFFORD GP, MURDOCH C. Porphyromonas gingivalis outer membrane vesicles increase vascular permeability[J]. Journal of Dental Research, 2020, 99(13): 1494-1501.
    [54] NONAKA S, KADOWAKI T, NAKANISHI H. Secreted gingipains from Porphyromonas gingivalis increase permeability in human cerebral microvascular endothelial cells through intracellular degradation of tight junction proteins[J]. Neurochemistry International, 2022, 154: 105282.
    [55] FAN RY, ZHOU Y, CHEN X, ZHONG XM, HE FZ, PENG WZ, LI L, WANG XQ, XU Y. Porphyromonas gingivalis outer membrane vesicles promote apoptosis via msRNA-regulated DNA methylation in periodontitis[J]. Microbiology Spectrum, 2023, 11(1): e0328822.
    [56] FURUTA N, TAKEUCHI H, AMANO A. Entry of Porphyromonas gingivalis outer membrane vesicles into epithelial cells causes cellular functional impairment[J]. Infection and Immunity, 2009, 77(11): 4761-4770.
    [57] INOUE E, MINATOZAKI S, SHIMIZU S, MIYAMOTO S, JO M, NI JJ, TOZAKI-SAITOH H, ODA K, NONAKA S, NAKANISHI H. Human β-defensin 3 inhibition of P. gingivalis LPS-induced IL-1β production by BV-2 microglia through suppression of cathepsins B and L[J]. Cells, 2024, 13(3): 283.
    [58] CAI YW, CHAI YH, FU Y, WANG YD, ZHANG YM, ZHANG X, ZHU LP, MIAO MX, YAN TH. Salidroside ameliorates Alzheimer’s disease by targeting NLRP3 inflammasome-mediated pyroptosis[J]. Frontiers in Aging Neuroscience, 2022, 13: 809433.
    [59] MAO HC, GONG T, SUN YT, YANG SY, QIAO X, YANG DQ. Bacterial growth stage determines the yields, protein composition, and periodontal pathogenicity of Porphyromonas gingivalis outer membrane vesicles[J]. Frontiers in Cellular and Infection Microbiology, 2023, 13: 1193198.
    [60] YOSHIDA K, YOSHIDA K, SEYAMA M, HIROSHIMA Y, MEKATA M, FUJIWARA N, KUDO Y, OZAKI K. Porphyromonas gingivalis outer membrane vesicles in cerebral ventricles activate microglia in mice[J]. Oral Diseases, 2023, 29(8): 3688-3697.
    [61] MA XY, SHIN YJ, YOO JW, PARK HS, KIM DH. Extracellular vesicles derived from Porphyromonas gingivalis induce trigeminal nerve-mediated cognitive impairment[J]. Journal of Advanced Research, 2023, 54: 293-303.
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任欢,乔新,王峥,杨德琴. 牙龈卟啉单胞菌与阿尔茨海默病相关性致病机制[J]. 微生物学通报, 2024, 51(11): 4359-4369

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  • 收稿日期:2024-02-28
  • 录用日期:2024-03-31
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