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Targeting NLRP3 inflammasome for neurodegenerative disorders

Molecular Psychiatry volume 28, pages 4512–4527 (2023)Cite this article

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A Correction to this article was published on 20 November 2023

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Abstract

Neuroinflammation is a key pathological feature in neurological diseases, including Alzheimer’s disease (AD). The nucleotide-binding domain leucine-rich repeat-containing proteins (NLRs) belong to the pattern recognition receptors (PRRs) family that sense stress signals, which play an important role in inflammation. As a member of NLRs, the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) is predominantly expressed in microglia, the principal innate immune cells in the central nervous system (CNS). Microglia release proinflammatory cytokines to cause pyroptosis through activating NLRP3 inflammasome. The active NLRP3 inflammasome is involved in a variety of neurodegenerative diseases (NDs). Recent studies also indicate the key role of neuronal NLRP3 in the pathogenesis of neurological disorders. In this article, we reviewed the mechanisms of NLRP3 expression and activation and discussed the role of active NLRP3 inflammasome in the pathogenesis of NDs, particularly focusing on AD. The studies suggest that targeting NLRP3 inflammasome could be a novel approach for the disease modification.

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Fig. 1: Human NLRP3 gene and protein diagram.
Fig. 2: The canonical pathway of the NLRP3 inflammasome activation.
Fig. 3: The effect of Aβ on synaptic transmission.
Fig. 4: NLRP3-mediated glia cells contribute to neuronal dysfunction.

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References

  1. Hoffman HM, Wright FA, Broide DH, Wanderer AA, Kolodner RD. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet. 2000;66:1693–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Yanagisawa S, Katoh H, Imai T, Nomura S, Watanabe M. The relationship between inflammasomes and the endoplasmic reticulum stress response in the injured spinal cord. Neurosci Lett. 2019;705:54–59.

    CAS  PubMed  Google Scholar 

  3. Alfonso-Loeches S, Urena-Peralta JR, Morillo-Bargues MJ, Oliver-De La Cruz J, Guerri C. Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells. Front Cell Neurosci. 2014;8:216.

    PubMed  PubMed Central  Google Scholar 

  4. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.

    CAS  PubMed  Google Scholar 

  5. Mayor A, Martinon F, De Smedt T, Petrilli V, Tschopp J. A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses. Nat Immunol. 2007;8:497–503.

    CAS  PubMed  Google Scholar 

  6. de Alba E. Structure and interdomain dynamics of apoptosis-associated speck-like protein containing a CARD (ASC). J Biol Chem. 2009;284:32932–41.

    PubMed  PubMed Central  Google Scholar 

  7. Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK, Vos MR, et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell. 2014;156:1193–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kostura MJ, Tocci MJ, Limjuco G, Chin J, Cameron P, Hillman AG, et al. Identification of a monocyte specific pre-interleukin 1 beta convertase activity. Proc Natl Acad Sci USA. 1989;86:5227–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res. 2015;25:1285–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q, et al. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature. 2019;570:338–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Li X, Thome S, Ma X, Amrute-Nayak M, Finigan A, Kitt L, et al. MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism. Nat Commun. 2017;8:15986.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Lang T, Lee JPW, Elgass K, Pinar AA, Tate MD, Aitken EH, et al. Macrophage migration inhibitory factor is required for NLRP3 inflammasome activation. Nat Commun. 2018;9:2223.

    PubMed  PubMed Central  Google Scholar 

  13. Mohamed IN, Hafez SS, Fairaq A, Ergul A, Imig JD, El-Remessy AB. Thioredoxin-interacting protein is required for endothelial NLRP3 inflammasome activation and cell death in a rat model of high-fat diet. Diabetologia. 2014;57:413–23.

    CAS  PubMed  Google Scholar 

  14. Park S, Juliana C, Hong S, Datta P, Hwang I, Fernandes-Alnemri T, et al. The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J Immunol. 2013;191:4358–66.

    CAS  PubMed  Google Scholar 

  15. Samir P, Kesavardhana S, Patmore DM, Gingras S, Malireddi RKS, Karki R, et al. DDX3X acts as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome. Nature. 2019;573:590–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493:674–8.

    CAS  PubMed  Google Scholar 

  17. Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, et al. Inflammasome inhibition prevents alpha-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 2018;10:eaah4066.

    PubMed  PubMed Central  Google Scholar 

  18. Mulazzani E, Wagner D, Havla J, Schluter M, Meinl I, Gerdes LA, et al. Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants. J Neuroinflammation. 2020;17:196.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Park K, Shen BW, Parmeggiani F, Huang PS, Stoddard BL, Baker D. Control of repeat-protein curvature by computational protein design. Nat Struct Mol Biol. 2015;22:167–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Duan Y, Wang J, Cai J, Kelley N, He Y. The leucine-rich repeat (LRR) domain of NLRP3 is required for NLRP3 inflammasome activation in macrophages. J Biol Chem. 2022;298:102717.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Theodoropoulou K, Spel L, Zaffalon L, Delacretaz M, Hofer M, Martinon F. NLRP3 leucine-rich repeats control induced and spontaneous inflammasome activation in cryopyrin-associated periodic syndrome. J Allergy Clin Immunol. 2023;151:222–32.e229.

    CAS  PubMed  Google Scholar 

  22. Andreeva L, David L, Rawson S, Shen C, Pasricha T, Pelegrin P, et al. NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation. Cell. 2021;184:6299–312.e6222.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Fletcher DJ. Coping with insomnia. Helping patients manage sleeplessness without drugs. Postgrad Med. 1986;79:265–74.

    CAS  PubMed  Google Scholar 

  24. Hoss F, Mueller JL, Rojas Ringeling F, Rodriguez-Alcazar JF, Brinkschulte R, Seifert G, et al. Alternative splicing regulates stochastic NLRP3 activity. Nat Commun. 2019;10:3238.

    PubMed  PubMed Central  Google Scholar 

  25. Ji X, Song Z, He J, Guo S, Chen Y, Wang H, et al. NIMA-related kinase 7 amplifies NLRP3 inflammasome pro-inflammatory signaling in microglia/macrophages and mice models of spinal cord injury. Exp Cell Res. 2021;398:112418.

    CAS  PubMed  Google Scholar 

  26. Luo K, Yang L, Liu Y, Wang ZF, Zhuang K. HDAC inhibitor SAHA alleviates pyroptosis by up-regulating miR-340 to inhibit NEK7 signaling in subarachnoid hemorrhage. Neurochem Res. 2023;48:458–70.

    CAS  PubMed  Google Scholar 

  27. Li C, Lin H, He H, Ma M, Jiang W, Zhou R. Inhibition of the NLRP3 inflammasome activation by manoalide ameliorates experimental autoimmune encephalomyelitis pathogenesis. Front Cell Dev Biol. 2022;10:822236.

    PubMed  PubMed Central  Google Scholar 

  28. Li G, Dong Y, Liu D, Zou Z, Hao G, Gao X, et al. NEK7 coordinates rapid neuroinflammation after subarachnoid hemorrhage in Mice. Front Neurol. 2020;11:551.

    PubMed  PubMed Central  Google Scholar 

  29. Chen Y, Meng J, Bi F, Li H, Chang C, Ji C, et al. EK7 regulates NLRP3 inflammasome activation and neuroinflammation post-traumatic brain injury. Front Mol Neurosci. 2019;12:202.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. de la Rosa G, Gomez AI, Banos MC, Pelegrin P. Signaling through purinergic receptor P2Y(2) enhances macrophage IL-1beta production. Int J Mol Sci. 2020;21:4686.

    PubMed  PubMed Central  Google Scholar 

  31. Moraes-Vieira PM, Yore MM, Sontheimer-Phelps A, Castoldi A, Norseen J, Aryal P, et al. Retinol binding protein 4 primes the NLRP3 inflammasome by signaling through Toll-like receptors 2 and 4. Proc Natl Acad Sci USA. 2020;117:31309–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Briard B, Fontaine T, Samir P, Place DE, Muszkieta L, Malireddi RKS, et al. Galactosaminogalactan activates the inflammasome to provide host protection. Nature. 2020;588:688–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Rodrigues TS, de Sa KSG, Ishimoto AY, Becerra A, Oliveira S, Almeida L, et al. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. J Exp Med. 2021;218:e20201707.

    CAS  PubMed  Google Scholar 

  34. Huang R, Hou L, Zhai X, Ruan Z, Sun W, Zhang D, et al. 2,5-hexanedione induces NLRP3 inflammasome activation and neurotoxicity through NADPH oxidase-dependent pathway. Free Radic Biol Med. 2020;162:561–70.

    PubMed  Google Scholar 

  35. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004;20:319–25.

    CAS  PubMed  Google Scholar 

  36. Chen S, Wang Y, Pan Y, Liu Y, Zheng S, Ding K, et al. Novel role for tranilast in regulating NLRP3 ubiquitination, vascular inflammation, and atherosclerosis. J Am Heart Assoc. 2020;9:e015513.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Tang J, Tu S, Lin G, Guo H, Yan C, Liu Q, et al. Sequential ubiquitination of NLRP3 by RNF125 and Cbl-b limits inflammasome activation and endotoxemia. J Exp Med. 2020;217:e20182091.

    PubMed  PubMed Central  Google Scholar 

  38. Xu T, Yu W, Fang H, Wang Z, Chi Z, Guo X, et al. Ubiquitination of NLRP3 by gp78/Insig-1 restrains NLRP3 inflammasome activation. Cell Death Differ. 2022;29:1582–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Song H, Zhao C, Yu Z, Li Q, Yan R, Qin Y, et al. UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression. Nat Commun. 2020;11:6042.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Py BF, Kim MS, Vakifahmetoglu-Norberg H, Yuan J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol Cell. 2013;49:331–8.

    CAS  PubMed  Google Scholar 

  41. Ren G, Zhang X, Xiao Y, Zhang W, Wang Y, Ma W, et al. ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination. EMBO J. 2019;38:e100376.

    PubMed  PubMed Central  Google Scholar 

  42. Bednash JS, Johns F, Patel N, Smail TR, Londino JD, Mallampalli RK. The deubiquitinase STAMBP modulates cytokine secretion through the NLRP3 inflammasome. Cell Signal. 2021;79:109859.

    CAS  PubMed  Google Scholar 

  43. Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, et al. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell. 2015;160:62–73.

    CAS  PubMed  Google Scholar 

  44. Stutz A, Kolbe CC, Stahl R, Horvath GL, Franklin BS, van Ray O, et al. NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. J Exp Med. 2017;214:1725–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Fischer FA, Mies LFM, Nizami S, Pantazi E, Danielli S, Demarco B, et al. TBK1 and IKKepsilon act like an OFF switch to limit NLRP3 inflammasome pathway activation. Proc Natl Acad Sci USA. 2021;118:e2009309118.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Niu T, De Rosny C, Chautard S, Rey A, Patoli D, Groslambert M, et al. NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly. Nat Commun. 2021;12:5862.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Mezzasoma L, Talesa VN, Romani R, Bellezza I. ANP and BNP exert anti-inflammatory action via NPR-1/cGMP axis by interfering with canonical, non-canonical, and alternative routes of inflammasome activation in human THP1 cells. Int J Mol Sci. 2020;22:24.

    PubMed  PubMed Central  Google Scholar 

  48. Zhang Z, Meszaros G, He WT, Xu Y, de Fatima Magliarelli H, Mailly L, et al. Protein kinase D at the Golgi controls NLRP3 inflammasome activation. J Exp Med. 2017;214:2671–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Song N, Liu ZS, Xue W, Bai ZF, Wang QY, Dai J, et al. NLRP3 phosphorylation is an essential priming event for inflammasome activation. Mol Cell. 2017;68:185–97.e186.

    CAS  PubMed  Google Scholar 

  50. Barry R, John SW, Liccardi G, Tenev T, Jaco I, Chen CH, et al. SUMO-mediated regulation of NLRP3 modulates inflammasome activity. Nat Commun. 2018;9:3001.

    PubMed  PubMed Central  Google Scholar 

  51. He M, Chiang HH, Luo H, Zheng Z, Qiao Q, Wang L, et al. An acetylation switch of the NLRP3 inflammasome regulates aging-associated chronic inflammation and insulin resistance. Cell Metab. 2020;31:580–91.e585.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang W, Hu D, Feng Y, Wu C, Song Y, Liu W, et al. Paxillin mediates ATP-induced activation of P2X7 receptor and NLRP3 inflammasome. BMC Biol. 2020;18:182.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Yaron JR, Gangaraju S, Rao MY, Kong X, Zhang L, Su F, et al. K(+) regulates Ca(2+) to drive inflammasome signaling: dynamic visualization of ion flux in live cells. Cell Death Dis. 2015;6:e1954.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 2007;14:1583–9.

    CAS  PubMed  Google Scholar 

  55. Green JP, Yu S, Martin-Sanchez F, Pelegrin P, Lopez-Castejon G, Lawrence CB, et al. Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming. Proc Natl Acad Sci USA. 2018;115:E9371–E9380.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM, Nunez G. K(+) efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 2013;38:1142–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Tang T, Lang X, Xu C, Wang X, Gong T, Yang Y, et al. CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation. Nat Commun. 2017;8:202.

    PubMed  PubMed Central  Google Scholar 

  58. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9:847–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Lauterbach MA, Saavedra V, Mangan MSJ, Penno A, Thiele C, Latz E et al. 1-Deoxysphingolipids cause autophagosome and lysosome accumulation and trigger NLRP3 inflammasome activation. Autophagy. 2021;17:1947–61.

  60. Li L, Gao P, Tang X, Liu Z, Cao M, Luo R, et al. CB1R-stabilized NLRP3 inflammasome drives antipsychotics cardiotoxicity. Signal Transduct Target Ther. 2022;7:190.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Yu S, Green J, Wellens R, Lopez-Castejon G, Brough D. Bafilomycin A1 enhances NLRP3 inflammasome activation in human monocytes independent of lysosomal acidification. FEBS J. 2021;288:3186–96.

    CAS  PubMed  Google Scholar 

  62. Gross CJ, Mishra R, Schneider KS, Medard G, Wettmarshausen J, Dittlein DC, et al. K(+) efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria. Immunity. 2016;45:761–73.

    CAS  PubMed  Google Scholar 

  63. Dagvadorj J, Mikulska-Ruminska K, Tumurkhuu G, Ratsimandresy RA, Carriere J, Andres AM, et al. Recruitment of pro-IL-1alpha to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation. Proc Natl Acad Sci USA. 2021;118:e2015632118.

    CAS  PubMed  Google Scholar 

  64. Pereira CA, Carlos D, Ferreira NS, Silva JF, Zanotto CZ, Zamboni DS, et al. Mitochondrial DNA promotes NLRP3 inflammasome activation and contributes to endothelial dysfunction and inflammation in type 1 diabetes. Front Physiol. 2019;10:1557.

    PubMed  Google Scholar 

  65. Chen J, Chen ZJ. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature. 2018;564:71–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479:117–21.

    CAS  PubMed  Google Scholar 

  67. Moretti J, Jia B, Hutchins Z, Roy S, Yip H, Wu J, et al. Caspase-11 interaction with NLRP3 potentiates the noncanonical activation of the NLRP3 inflammasome. Nat Immunol. 2022;23:705–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526:666–71.

    CAS  PubMed  Google Scholar 

  69. Compan V, Baroja-Mazo A, Lopez-Castejon G, Gomez AI, Martinez CM, Angosto D, et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity. 2012;37:487–500.

    CAS  PubMed  Google Scholar 

  70. Green JP, Swanton T, Morris LV, El-Sharkawy LY, Cook J, Yu S, et al. LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation. Elife. 2020;9:e59704.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Li JY, Wang YY, Shao T, Fan DD, Lin AF, Xiang LX, et al. The zebrafish NLRP3 inflammasome has functional roles in ASC-dependent interleukin-1beta maturation and gasdermin E-mediated pyroptosis. J Biol Chem. 2020;295:1120–41.

    PubMed  Google Scholar 

  72. Zhou B, Abbott DW. Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases. Cell Rep. 2021;35:108998.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Yao F, Jin Z, Zheng Z, Lv X, Ren L, Yang J, et al. HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells. Cell Death Discov. 2022;8:112.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Andres KH, von During M, Muszynski K, Schmidt RF. Nerve fibres and their terminals of the dura mater encephali of the rat. Anat Embryol. 1987;175:289–301.

    CAS  Google Scholar 

  75. Foldi M, Gellert A, Kozma M, Poberai M, Zoltan OT, Csanda E. New contributions to the anatomical connections of the brain and the lymphatic system. Acta Anat. 1966;64:498–505.

    CAS  PubMed  Google Scholar 

  76. Baroja-Mazo A, Martin-Sanchez F, Gomez AI, Martinez CM, Amores-Iniesta J, Compan V, et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol. 2014;15:738–48.

    CAS  PubMed  Google Scholar 

  77. Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A, Engels G, et al. The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat Immunol. 2014;15:727–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, et al. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegener. 2016;11:23.

    PubMed  PubMed Central  Google Scholar 

  79. von Herrmann KM, Salas LA, Martinez EM, Young AL, Howard JM, Feldman MS, et al. NLRP3 expression in mesencephalic neurons and characterization of a rare NLRP3 polymorphism associated with decreased risk of Parkinson’s disease. NPJ Parkinsons Dis. 2018;4:24.

    Google Scholar 

  80. Johann S, Heitzer M, Kanagaratnam M, Goswami A, Rizo T, Weis J, et al. NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia. 2015;63:2260–73.

    PubMed  Google Scholar 

  81. Malhotra S, Costa C, Eixarch H, Keller CW, Amman L, Martinez-Banaclocha H, et al. NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients. Brain. 2020;143:1414–30.

    PubMed  Google Scholar 

  82. Wallisch JS, Simon DW, Bayir H, Bell MJ, Kochanek PM, Clark RSB. Cerebrospinal fluid NLRP3 is increased after severe traumatic brain injury in infants and children. Neurocrit Care. 2017;27:44–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Wang H, Xu P, Liao D, Dang R, He X, Guo Y, et al. Association between NLPR1, NLPR3, and P2X7R gene polymorphisms with partial seizures. Biomed Res Int. 2017;2017:9547902.

    PubMed  PubMed Central  Google Scholar 

  84. Swaroop S, Mahadevan A, Shankar SK, Adlakha YK, Basu A. HSP60 critically regulates endogenous IL-1beta production in activated microglia by stimulating NLRP3 inflammasome pathway. J Neuroinflammation. 2018;15:177.

    PubMed  PubMed Central  Google Scholar 

  85. Fan Z, Pan YT, Zhang ZY, Yang H, Yu SY, Zheng Y, et al. Systemic activation of NLRP3 inflammasome and plasma alpha-synuclein levels are correlated with motor severity and progression in Parkinson’s disease. J Neuroinflammation. 2020;17:11.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Peng Y, Chen J, Dai Y, Jiang Y, Qiu W, Gu Y, et al. NLRP3 level in cerebrospinal fluid of patients with neuromyelitis optica spectrum disorders: Increased levels and association with disease severity. Mult Scler Relat Disord. 2019;39:101888.

    PubMed  Google Scholar 

  87. Cristina de Brito Toscano E, Leandro Marciano Vieira E, Boni Rocha Dias B, Vidigal Caliari M, Paula Goncalves A, Varela Giannetti A, et al. NLRP3 and NLRP1 inflammasomes are up-regulated in patients with mesial temporal lobe epilepsy and may contribute to overexpression of caspase-1 and IL-beta in sclerotic hippocampi. Brain Res. 2020;1752:147230.

    PubMed  Google Scholar 

  88. Liu Y, Dai Y, Li Q, Chen C, Chen H, Song Y, et al. Beta-amyloid activates NLRP3 inflammasome via TLR4 in mouse microglia. Neurosci Lett. 2020;736:135279.

    CAS  PubMed  Google Scholar 

  89. Gustot A, Gallea JI, Sarroukh R, Celej MS, Ruysschaert JM, Raussens V. Amyloid fibrils are the molecular trigger of inflammation in Parkinson’s disease. Biochem J. 2015;471:323–33.

    CAS  PubMed  Google Scholar 

  90. Deora V, Lee JD, Albornoz EA, McAlary L, Jagaraj CJ, Robertson AAB, et al. The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia. 2020;68:407–21.

    PubMed  Google Scholar 

  91. Panicker N, Kam TI, Wang H, Neifert S, Chou SC, Kumar M, et al. Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’s disease. Neuron. 2022;110:2422–37.e2429.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Zengeler KE, Lukens JR. Taking the parkin brakes off of neuronal NLRP3 drives inflammasome activation and neurodegeneration in Parkinson’s disease. Neuron. 2022;110:2356–8.

    CAS  PubMed  Google Scholar 

  93. Quan W, Luo Q, Tang Q, Furihata T, Li D, Fassbender K, et al. NLRP3 is involved in the maintenance of cerebral pericytes. Front Cell Neurosci. 2020;14:276.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang S, Cai F, Wu Y, Bozorgmehr T, Wang Z, Zhang S, et al. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol Psychiatry. 2020;25:603–13.

    CAS  PubMed  Google Scholar 

  95. Zhang Y, Song W. Islet amyloid polypeptide: Another key molecule in Alzheimer’s pathogenesis? Prog Neurobiol. 2017;153:100–20.

    CAS  PubMed  Google Scholar 

  96. Zhang S, Zhao J, Zhang Y, Zhang Y, Cai F, Wang L, et al. Upregulation of MIF as a defense mechanism and a biomarker of Alzheimer’s disease. Alzheimers Res Ther. 2019;11:54.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, et al. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature. 2017;552:355–61.

    CAS  PubMed  Google Scholar 

  98. Zhang X, Wang R, Hu D, Sun X, Fujioka H, Lundberg K, et al. Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease. Sci Adv. 2020;6:eabb8680.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA. 1989;86:7611–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9:857–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Luciunaite A, McManus RM, Jankunec M, Racz I, Dansokho C, Dalgediene I, et al. Soluble Abeta oligomers and protofibrils induce NLRP3 inflammasome activation in microglia. J Neurochem. 2020;155:650–61.

    CAS  PubMed  Google Scholar 

  102. Nakanishi A, Kaneko N, Takeda H, Sawasaki T, Morikawa S, Zhou W, et al. Amyloid beta directly interacts with NLRP3 to initiate inflammasome activation: identification of an intrinsic NLRP3 ligand in a cell-free system. Inflamm Regen. 2018;38:27.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013;14:812–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Parajuli B, Sonobe Y, Horiuchi H, Takeuchi H, Mizuno T, Suzumura A. Oligomeric amyloid beta induces IL-1beta processing via production of ROS: implication in Alzheimer’s disease. Cell Death Dis. 2013;4:e975.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Krishnan D, Menon RN, Mathuranath PS, Gopala S. A novel role for SHARPIN in amyloid-beta phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease. Neurobiol Aging. 2020;93:131–41.

    CAS  PubMed  Google Scholar 

  106. Stancu IC, Cremers N, Vanrusselt H, Couturier J, Vanoosthuyse A, Kessels S, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019;137:599–617.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, et al. NLRP3 inflammasome activation drives tau pathology. Nature. 2019;575:669–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Panda C, Voelz C, Habib P, Mevissen C, Pufe T, Beyer C, et al. Aggregated Tau-PHF6 (VQIVYK) potentiates NLRP3 inflammasome expression and autophagy in human microglial cells. Cells. 2021;10:1652.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Jiang S, Maphis NM, Binder J, Chisholm D, Weston L, Duran W, et al. Proteopathic tau primes and activates interleukin-1beta via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway. Cell Rep. 2021;36:109720.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Silva DF, Candeias E, Esteves AR, Magalhaes JD, Ferreira IL, Nunes-Costa D, et al. Microbial BMAA elicits mitochondrial dysfunction, innate immunity activation, and Alzheimer’s disease features in cortical neurons. J Neuroinflammation. 2020;17:332.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Li G, Wang Y, Cao F, Wang D, Zhou L, Jin Y. Sevoflurane promotes neurodegeneration through inflammasome formation in APP/PS1 mice. Front Neurosci. 2021;15:647136.

    PubMed  PubMed Central  Google Scholar 

  112. Delarasse C, Auger R, Gonnord P, Fontaine B, Kanellopoulos JM. The purinergic receptor P2X7 triggers alpha-secretase-dependent processing of the amyloid precursor protein. J Biol Chem. 2011;286:2596–606.

    CAS  PubMed  Google Scholar 

  113. Karmakar M, Katsnelson MA, Dubyak GR, Pearlman E. Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1beta secretion in response to ATP. Nat Commun. 2016;7:10555.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Shen H, Guan Q, Zhang X, Yuan C, Tan Z, Zhai L, et al. New mechanism of neuroinflammation in Alzheimer’s disease: the activation of NLRP3 inflammasome mediated by gut microbiota. Prog Neuropsychopharmacol Biol Psychiatry. 2020;100:109884.

    CAS  PubMed  Google Scholar 

  115. Zhao Y, Zeng CY, Li XH, Yang TT, Kuang X, Du JR. Klotho overexpression improves amyloid-beta clearance and cognition in the APP/PS1 mouse model of Alzheimer’s disease. Aging Cell. 2020;19:e13239.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Moonen S, Koper MJ, Van Schoor E, Schaeverbeke JM, Vandenberghe R, von Arnim CAF, et al. Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons. Acta Neuropathol. 2023;145:175–95.

    CAS  PubMed  Google Scholar 

  117. Qi Y, Klyubin I, Cuello AC, Rowan MJ. NLRP3-dependent synaptic plasticity deficit in an Alzheimer’s disease amyloidosis model in vivo. Neurobiol Dis. 2018;114:24–30.

    CAS  PubMed  Google Scholar 

  118. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Tran TTT, Corsini S, Kellingray L, Hegarty C, Le Gall G, Narbad A, et al. APOE genotype influences the gut microbiome structure and function in humans and mice: relevance for Alzheimer’s disease pathophysiology. FASEB J. 2019;33:8221–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Yin C, Ackermann S, Ma Z, Mohanta SK, Zhang C, Li Y, et al. Publisher correction: ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med. 2019;25:529.

    CAS  PubMed  Google Scholar 

  121. Rawat P, Teodorof-Diedrich C, Spector SA. Human immunodeficiency virus Type-1 single-stranded RNA activates the NLRP3 inflammasome and impairs autophagic clearance of damaged mitochondria in human microglia. Glia. 2019;67:802–24.

    PubMed  Google Scholar 

  122. Qi Y, Klyubin I, Harney SC, Hu N, Cullen WK, Grant MK, et al. Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Ass-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Ass agents. Acta Neuropathol Commun. 2014;2:175.

    PubMed  PubMed Central  Google Scholar 

  123. Zhang Y, Dong Z, Song W. NLRP3 inflammasome as a novel therapeutic target for Alzheimer’s disease. Signal Transduct Target Ther. 2020;5:37.

    PubMed  PubMed Central  Google Scholar 

  124. Chatterjee K, Roy A, Banerjee R, Choudhury S, Mondal B, Halder S, et al. Inflammasome and alpha-synuclein in Parkinson’s disease: a cross-sectional study. J Neuroimmunol. 2020;338:577089.

    CAS  PubMed  Google Scholar 

  125. Wang X, Chi J, Huang D, Ding L, Zhao X, Jiang L, et al. alpha-synuclein promotes progression of Parkinson’s disease by upregulating autophagy signaling pathway to activate NLRP3 inflammasome. Exp Ther Med. 2020;19:931–8.

    CAS  PubMed  Google Scholar 

  126. Han X, Sun S, Sun Y, Song Q, Zhu J, Song N, et al. Small molecule-driven NLRP3 inflammation inhibition via interplay between ubiquitination and autophagy: implications for Parkinson disease. Autophagy. 2019;15:1860–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Mao Z, Liu C, Ji S, Yang Q, Ye H, Han H, et al. The NLRP3 Inflammasome is Involved in the Pathogenesis of Parkinson’s Disease in Rats. Neurochem Res. 2017;42:1104–15.

    CAS  PubMed  Google Scholar 

  128. Solini A, Rossi C, Santini E, Giuntini M, Raggi F, Parolini F, et al. P2X7 receptor/NLRP3 inflammasome complex and alpha-synuclein in peripheral blood mononuclear cells: a prospective study in neo-diagnosed, treatment-naive Parkinson’s disease. Eur J Neurol. 2021;28:2648–56.

    PubMed  Google Scholar 

  129. Roy A, Banerjee R, Choudhury S, Chatterjee K, Mondal B, Dey S, et al. Novel inflammasome and oxidative modulators in Parkinson’s disease: a prospective study. Neurosci Lett. 2022;786:136768.

    CAS  PubMed  Google Scholar 

  130. Cao B, Wang T, Qu Q, Kang T, Yang Q. Long noncoding RNA SNHG1 promotes neuroinflammation in Parkinson’s disease via regulating miR-7/NLRP3 pathway. Neuroscience. 2018;388:118–27.

    CAS  PubMed  Google Scholar 

  131. Trudler D, Nazor KL, Eisele YS, Grabauskas T, Dolatabadi N, Parker J, et al. Soluble alpha-synuclein-antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proc Natl Acad Sci USA. 2021;118:e2025847118.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Piancone F, Saresella M, La Rosa F, Marventano I, Meloni M, Navarro J, et al. Inflammatory responses to monomeric and aggregated alpha-synuclein in peripheral blood of Parkinson disease patients. Front Neurosci. 2021;15:639646.

    PubMed  PubMed Central  Google Scholar 

  133. Scheiblich H, Bousset L, Schwartz S, Griep A, Latz E, Melki R, et al. Microglial NLRP3 inflammasome activation upon TLR2 and TLR5 ligation by distinct alpha-synuclein assemblies. J Immunol. 2021;207:2143–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Mouton-Liger F, Rosazza T, Sepulveda-Diaz J, Ieang A, Hassoun SM, Claire E, et al. Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20-dependent negative feedback loop. Glia. 2018;66:1736–51.

    PubMed  PubMed Central  Google Scholar 

  135. Ge X, Cai F, Shang Y, Chi F, Xiao H, Xu J, et al. PARK2 attenuates house dust mite-induced inflammatory reaction, pyroptosis and barrier dysfunction in BEAS-2B cells by ubiquitinating NLRP3. Am J Transl Res. 2021;13:326–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8.

    CAS  PubMed  Google Scholar 

  137. Lee E, Hwang I, Park S, Hong S, Hwang B, Cho Y, et al. MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration. Cell Death Differ. 2019;26:213–28.

    CAS  PubMed  Google Scholar 

  138. Javed H, Thangavel R, Selvakumar GP, Dubova I, Schwartz N, Ahmed ME, et al. NLRP3 inflammasome and glia maturation factor coordinately regulate neuroinflammation and neuronal loss in MPTP mouse model of Parkinson’s disease. Int Immunopharmacol. 2020;83:106441.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Pike AF, Longhena F, Faustini G, van Eik JM, Gombert I, Herrebout MAC, et al. Dopamine signaling modulates microglial NLRP3 inflammasome activation: implications for Parkinson’s disease. J Neuroinflammation. 2022;19:50.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Chen J, Mao K, Yu H, Wen Y, She H, Zhang H, et al. p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson’s disease. J Neuroinflammation. 2021;18:295.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Qin Y, Qiu J, Wang P, Liu J, Zhao Y, Jiang F, et al. Impaired autophagy in microglia aggravates dopaminergic neurodegeneration by regulating NLRP3 inflammasome activation in experimental models of Parkinson’s disease. Brain Behav Immun. 2021;91:324–38.

    CAS  PubMed  Google Scholar 

  142. Cheng J, Liao Y, Dong Y, Hu H, Yang N, Kong X, et al. Microglial autophagy defect causes Parkinson disease-like symptoms by accelerating inflammasome activation in mice. Autophagy. 2020;16:2193–205.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Sarkar S, Malovic E, Harishchandra DS, Ghaisas S, Panicker N, Charli A, et al. Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson’s disease. NPJ Parkinsons Dis. 2017;3:30.

    PubMed  PubMed Central  Google Scholar 

  144. Grotemeyer A, Fischer JF, Koprich JB, Brotchie JM, Blum R, Volkmann J, et al. Inflammasome inhibition protects dopaminergic neurons from alpha-synuclein pathology in a model of progressive Parkinson’s disease. J Neuroinflammation. 2023;20:79.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen ZD, Zhao L, Chen HY, Gong JN, Chen X, Chen CY. A novel artificial intelligence protocol to investigate potential leads for Parkinson’s disease. RSC Adv. 2020;10:22939–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Van Schoor E, Ospitalieri S, Moonen S, Tome SO, Ronisz A, Ok O, et al. Increased pyroptosis activation in white matter microglia is associated with neuronal loss in ALS motor cortex. Acta Neuropathol. 2022;144:393–411.

    PubMed  Google Scholar 

  147. Zhang H, Li H, Huang B, Wang S, Gao Y, Meng F, et al. Spatiotemporal evolution of pyroptosis and canonical inflammasome pathway in hSOD1(G93A) ALS mouse model. BMC Neurosci. 2022;23:50.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhao W, Beers DR, Bell S, Wang J, Wen S, Baloh RH, et al. TDP-43 activates microglia through NF-kappaB and NLRP3 inflammasome. Exp Neurol. 2015;273:24–35.

    CAS  PubMed  Google Scholar 

  149. Zhuang J, Wen X, Zhang YQ, Shan Q, Zhang ZF, Zheng GH, et al. TDP-43 upregulation mediated by the NLRP3 inflammasome induces cognitive impairment in 2 2’,4,4’-tetrabromodiphenyl ether (BDE-47)-treated mice. Brain Behav Immun. 2017;65:99–110.

    CAS  PubMed  Google Scholar 

  150. Gugliandolo A, Giacoppo S, Bramanti P, Mazzon E. NLRP3 inflammasome activation in a transgenic amyotrophic lateral sclerosis model. Inflammation. 2018;41:93–103.

    CAS  PubMed  Google Scholar 

  151. Goldstein LH, Abrahams S. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol. 2013;12:368–80.

    PubMed  Google Scholar 

  152. Debye B, Schmulling L, Zhou L, Rune G, Beyer C, Johann S. Neurodegeneration and NLRP3 inflammasome expression in the anterior thalamus of SOD1(G93A) ALS mice. Brain Pathol. 2018;28:14–27.

    CAS  PubMed  Google Scholar 

  153. Banerjee P, Elliott E, Rifai OM, O’Shaughnessy J, McDade K, Abrahams S, et al. NLRP3 inflammasome as a key molecular target underlying cognitive resilience in amyotrophic lateral sclerosis. J Pathol. 2022;256:262–8.

    CAS  PubMed  Google Scholar 

  154. Moreno-Garcia L, Miana-Mena FJ, Moreno-Martinez L, de la Torre M, Lunetta C, Tarlarini C, et al. Inflammasome in ALS Skeletal Muscle: NLRP3 as a Potential Biomarker. Int J Mol Sci. 2021;22:2523.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11:323–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Fu RH, Tsai CW, Chiu SC, Liu SP, Chiang YT, Kuo YH, et al. C9-ALS-associated proline-arginine dipeptide repeat protein induces activation of NLRP3 inflammasome of HMC3 microglia cells by binding of complement component 1 Q subcomponent-binding protein (C1QBP), and syringin prevents this effect. Cells. 2022;11:3128.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Inoue M, Williams KL, Gunn MD, Shinohara ML. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 2012;109:10480–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Galloway DA, Carew SJ, Blandford SN, Benoit RY, Fudge NJ, Berry T, et al. Investigating the NLRP3 inflammasome and its regulator miR-223-3p in multiple sclerosis and experimental demyelination. J Neurochem. 2022;163:94–112.

    CAS  PubMed  Google Scholar 

  159. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364:2106–12.

    CAS  PubMed  Google Scholar 

  160. Takahashi T, Fujihara K, Nakashima I, Misu T, Miyazawa I, Nakamura M, et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain. 2007;130:1235–43.

    PubMed  Google Scholar 

  161. Liu HD, Li W, Chen ZR, Hu YC, Zhang DD, Shen W, et al. Expression of the NLRP3 inflammasome in cerebral cortex after traumatic brain injury in a rat model. Neurochem Res. 2013;38:2072–83.

    CAS  PubMed  Google Scholar 

  162. Liu XL, Sun DD, Zheng MT, Li XT, Niu HH, Zhang L, et al. Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes. Neural Regen Res. 2023;18:141–9.

    CAS  PubMed  Google Scholar 

  163. Zhang Y, Yao Z, Xiao Y, Zhang X, Liu J. Downregulated XBP-1 rescues cerebral ischemia/reperfusion injury-induced pyroptosis via the NLRP3/Caspase-1/GSDMD axis. Mediators Inflamm. 2022;2022:8007078.

    PubMed  PubMed Central  Google Scholar 

  164. Hu Y, Wang P, Han K. Hydrogen attenuated inflammation response and oxidative in hypoxic ischemic encephalopathy via Nrf2 mediated the inhibition of NLRP3 and NF-kappaB. Neuroscience. 2022;485:23–36.

    CAS  PubMed  Google Scholar 

  165. Li YQ, Chen JX, Li QW, Xiao ZJ, Yuan T, Xie ZH. Targeting NLRP3 inflammasome improved the neurogenesis and post-stroke cognition in a mouse model of photothrombotic stroke. Neuroreport. 2020;31:806–13.

    CAS  PubMed  Google Scholar 

  166. Tan SW, Zhao Y, Li P, Ning YL, Huang ZZ, Yang N, et al. HMGB1 mediates cognitive impairment caused by the NLRP3 inflammasome in the late stage of traumatic brain injury. J Neuroinflammation. 2021;18:241.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Vasconcellos LRC, Martimiano L, Dantas DP, Fonseca FM, Mata-Santos H, Travassos L, et al. Intracerebral injection of heme induces lipid peroxidation, neuroinflammation, and sensorimotor deficits. Stroke. 2021;52:1788–97.

    CAS  PubMed  Google Scholar 

  168. Pan T, Zhu QJ, Xu LX, Ding X, Li JQ, Sun B, et al. Knocking down TRPM2 expression reduces cell injury and NLRP3 inflammasome activation in PC12 cells subjected to oxygen-glucose deprivation. Neural Regen Res. 2020;15:2154–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Hu H, Zhu T, Gong L, Zhao Y, Shao Y, Li S, et al. Transient receptor potential melastatin 2 contributes to neuroinflammation and negatively regulates cognitive outcomes in a pilocarpine-induced mouse model of epilepsy. Int Immunopharmacol. 2020;87:106824.

    CAS  PubMed  Google Scholar 

  170. Adamczak S, Dale G, de Rivero Vaccari JP, Bullock MR, Dietrich WD, Keane RW. Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J Neurosurg. 2012;117:1119–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Moraes CA, Hottz ED, Dos Santos Ornellas D, Adesse D, de Azevedo CT, d’Avila JC, et al. Microglial NLRP3 inflammasome induces excitatory synaptic loss through IL-1beta-enriched microvesicle release: implications for sepsis-associated encephalopathy. Mol Neurobiol. 2023;60:481–94.

    CAS  PubMed  Google Scholar 

  172. Dempsey C, Rubio Araiz A, Bryson KJ, Finucane O, Larkin C, Mills EL, et al. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-beta and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017;61:306–16.

    CAS  PubMed  Google Scholar 

  173. Li K, Shi G, Zhao Y, Chen Y, Gao J, Yao L, et al. Electroacupuncture ameliorates neuroinflammation-mediated cognitive deficits through inhibition of NLRP3 in Presenilin1/2 conditional double knockout mice. Neural Plast. 2021;2021:8814616.

    PubMed  PubMed Central  Google Scholar 

  174. He XF, Xu JH, Li G, Li MY, Li LL, Pei Z, et al. NLRP3-dependent microglial training impaired the clearance of amyloid-beta and aggravated the cognitive decline in Alzheimer’s disease. Cell Death Dis. 2020;11:849.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Li J, Zhuang L, Luo X, Liang J, Sun E, He Y. Protection of MCC950 against Alzheimer’s disease via inhibiting neuronal pyroptosis in SAMP8 mice. Exp Brain Res. 2020;238:2603–14.

    CAS  PubMed  Google Scholar 

  176. Li JM, Hu T, Zhou XN, Zhang T, Guo JH, Wang MY, et al. The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice. J Neuroinflammation. 2023;20:112.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Lonnemann N, Hosseini S, Marchetti C, Skouras DB, Stefanoni D, D’Alessandro A, et al. The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2020;117:32145–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Cai Y, Chai Y, Fu Y, Wang Y, Zhang Y, Zhang X, et al. Salidroside ameliorates Alzheimer’s disease by targeting NLRP3 inflammasome-mediated pyroptosis. Front Aging Neurosci. 2021;13:809433.

    CAS  PubMed  Google Scholar 

  179. Daniels MJ, Rivers-Auty J, Schilling T, Spencer NG, Watremez W, Fasolino V, et al. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nat Commun. 2016;7:12504.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Lee HJ, Park JH, Hoe HS. Idebenone regulates abeta and LPS-induced neurogliosis and cognitive function through inhibition of NLRP3 inflammasome/IL-1beta axis activation. Front Immunol. 2022;13:749336.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Shippy DC, Wilhelm C, Viharkumar PA, Raife TJ, Ulland TK. beta-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology. J Neuroinflammation. 2020;17:280.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Liu T, Wang L, Liang P, Wang X, Liu Y, Cai J, et al. USP19 suppresses inflammation and promotes M2-like macrophage polarization by manipulating NLRP3 function via autophagy. Cell Mol Immunol. 2021;18:2431–42.

    CAS  PubMed  Google Scholar 

  183. Cui W, Sun C, Ma Y, Wang S, Wang X, Zhang Y. Inhibition of TLR4 induces M2 microglial polarization and provides neuroprotection via the NLRP3 inflammasome in Alzheimer’s disease. Front Neurosci. 2020;14:444.

    PubMed  PubMed Central  Google Scholar 

  184. Stuve O, Weideman RA, McMahan DM, Jacob DA, Little BB. Diclofenac reduces the risk of Alzheimer’s disease: a pilot analysis of NSAIDs in two US veteran populations. Ther Adv Neurol Disord. 2020;13:1756286420935676.

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Rivers-Auty J, Mather AE, Peters R, Lawrence CB, Brough D. Anti-inflammatories in Alzheimer’s disease-potential therapy or spurious correlate? Brain Commun. 2020;2:fcaa109.

    PubMed  PubMed Central  Google Scholar 

  186. Zhang X, Zhang Y, Li R, Zhu L, Fu B, Yan T. Salidroside ameliorates Parkinson’s disease by inhibiting NLRP3-dependent pyroptosis. Aging. 2020;12:9405–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Jiang Z, Yin X, Wang M, Wang Y, Li F, Gao Y, et al. beta-Hydroxybutyrate alleviates pyroptosis in MPP(+)/MPTP-induced Parkinson’s disease models via inhibiting STAT3/NLRP3/GSDMD pathway. Int Immunopharmacol. 2022;113:109451.

    CAS  PubMed  Google Scholar 

  188. Ma X, Hao J, Wu J, Li Y, Cai X, Zheng Y. Prussian blue nanozyme as a pyroptosis inhibitor alleviates neurodegeneration. Adv Mater. 2022;34:e2106723.

    PubMed  Google Scholar 

  189. Wang K, Lu C, Wang T, Qiao C, Lu L, Wu D, et al. Hyperoside suppresses NLRP3 inflammasome in Parkinson’s disease via pituitary adenylate cyclase-activating polypeptide. Neurochem Int. 2022;152:105254.

    CAS  PubMed  Google Scholar 

  190. Ren Y, Wang Q, Yang Z, Feng L, Zhang Y. MCC950 ameliorates the dementia symptom at the early age of line M83 mouse and reduces hippocampal alpha-synuclein accumulation. Biochem Biophys Res Commun. 2022;611:23–30.

    CAS  PubMed  Google Scholar 

  191. Liu S, Wang S, Gu R, Che N, Wang J, Cheng J, et al. The XPO1 inhibitor KPT-8602 ameliorates Parkinson’s disease by inhibiting the NF-kappaB/NLRP3 pathway. Front Pharm. 2022;13:847605.

    CAS  Google Scholar 

  192. Dong AQ, Yang YP, Jiang SM, Yao XY, Qi D, Mao CJ, et al. Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson’s disease. Acta Pharm Sin. 2023;44:32–43.

    CAS  Google Scholar 

  193. Campagno KE, Mitchell CH. The P2X(7) receptor in microglial cells modulates the endolysosomal axis, autophagy, and phagocytosis. Front Cell Neurosci. 2021;15:645244.

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, et al. Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci. 2001;21:3017–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Krishnan KJ, Ratnaike TE, De Gruyter HL, Jaros E, Turnbull DM. Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer’s disease. Neurobiol Aging. 2012;33:2210–4.

    CAS  PubMed  Google Scholar 

  196. Wang L, Wang W, Zhang L, Dai P, Wang K, Hui H, et al. Oxygen-glucose deprivation inducing B1 RNA inhibits neuronal cells metabolic activity by NLRP3 and associated proinflammatory cytokines production. Neurosci Lett. 2015;588:147–53.

    CAS  PubMed  Google Scholar 

  197. Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, et al. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann Neurol. 2015;77:953–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Van Dyck CH, Nygaard HB, Chen K, Donohue MC, Raman R, Rissman RA, et al. Effect of AZD0530 on cerebral metabolic decline in Alzheimer disease: a randomized clinical trial. JAMA Neurol. 2019;76:1219–29.

    PubMed  PubMed Central  Google Scholar 

  199. Iannuzzi F, Sirabella R, Canu N, Maier TJ, Annunziato L, Matrone C. Fyn tyrosine kinase elicits amyloid precursor protein Tyr682 Phosphorylation in neurons from Alzheimer’s disease patients. Cells. 2020;9:1807.

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Li T, Martin E, Abada Y-S, Boucher C, Cès A, Youssef I, et al. Effects of chronic masitinib treatment in APPPS1dE9 transgenic mice modeling Alzheimer’s disease. J Alzheimers Dis. 2020;76:1339–45.

  201. Yu J, Yan Y, Gu Q, Kumar G, Yu H, Zhao Y, et al. Fasudil in combination with bone marrow stromal cells (BMSCs) attenuates Alzheimer’s disease-related changes through the regulation of the peripheral immune system. Front Aging Neurosci. 2018;10:216–216.

    PubMed  PubMed Central  Google Scholar 

  202. Kumar M, Bansal N. Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer’s disease: involvement of PI3-kinase, eNOS and NFκB. Behav Brain Res. 2018;351:4–16.

    CAS  PubMed  Google Scholar 

  203. Xin YL, Yu JZ, Yang XW, Liu CY, Li YH, Feng L, et al. FSD-C10: a more promising novel ROCK inhibitor than Fasudil for treatment of CNS autoimmunity. Biosci Rep. 2015;35:247.

    Google Scholar 

  204. Gu QF, Yu JZ, Wu H, Li YH, Liu CY, Feng L, et al. Therapeutic effect of Rho kinase inhibitor FSD-C10 in a mouse model of alzheimer’s disease. Exp Therapeutic Med. 2018;16:3929–38.

    Google Scholar 

  205. Fleischhacker WW, Buchgeher A, Schubert H. Memantine in the treatment of senile dementia of the Alzheimer type. Prog Neuropsychopharmacol Biol Psychiatry. 1986;10:87–93.

    CAS  PubMed  Google Scholar 

  206. Tampi RR, van Dyck CH. Memantine: efficacy and safety in mild-to-severe Alzheimer’s disease. Neuropsychiatr Dis Treat. 2007;3:245–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci USA. 2013;110:E2518–2527.

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Ghatak S, Dolatabadi N, Gao R, Wu Y, Scott H, Trudler D, et al. NitroSynapsin ameliorates hypersynchronous neural network activity in Alzheimer hiPSC models. Mol Psychiatry. 2021;26:5751–65.

    CAS  PubMed  Google Scholar 

  209. Matthews DC, Mao X, Dowd K, Tsakanikas D, Jiang CS, Meuser C, et al. Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer’s disease. Brain. 2021;144:3742–55.

    PubMed  PubMed Central  Google Scholar 

  210. Burns A, Rossor M, Hecker J, Gauthier S, Petit H, Möller HJ, et al. The effects of donepezil in Alzheimer’s disease - results from a multinational trial. Dement Geriatr Cogn Disord. 1999;10:237–44.

    CAS  PubMed  Google Scholar 

  211. Johannsen P, Salmon E, Hampel H, Xu Y, Richardson S, Qvitzau S, et al. Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer’s disease. CNS Drugs. 2006;20:311–25.

    CAS  PubMed  Google Scholar 

  212. Seltzer B, Zolnouni P, Nunez M, Goldman R, Kumar D, Ieni J, et al. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol. 2004;61:1852–6.

    PubMed  Google Scholar 

  213. Knight R, Khondoker M, Magill N, Stewart R, Landau S. A systematic review and meta-analysis of the effectiveness of acetylcholinesterase inhibitors and memantine in treating the cognitive symptoms of dementia. Dement Geriatr Cogn Disord. 2018;45:131–51.

    CAS  PubMed  Google Scholar 

  214. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. Br Med J. 2000;321:1445–9.

    CAS  Google Scholar 

  215. Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology. 2000;54:2269–76.

    CAS  PubMed  Google Scholar 

  216. Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: International randomised controlled trial. Br Med J. 1999;318:633–40.

    Google Scholar 

  217. Small GW, Kaufer D, Mendiondo MS, Quarg P, Spiegel R. Cognitive performance in Alzheimer’s disease patients receiving rivastigmine for up to 5 years. Int J Clin Pr. 2005;59:473–7.

    CAS  Google Scholar 

  218. Finkel SI, Mintzer JE, Dysken M, Krishnan KRR, Burt T, McRae T. A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer’s disease in outpatients treated with donepezil. Int J Geriat Psychiat. 2004;19:9–18.

    Google Scholar 

  219. Mowla A, Mosavinasab M, Pani A. Does fluoxetine have any effect on the cognition of patients with mild cognitive impairment? J Clin Psychopharm. 2007;27:67–70.

    CAS  Google Scholar 

  220. Bartels C, Wagner M, Wolfsgruber S, Ehrenreich H, Schneider A. Impact of SSRI therapy on risk of conversion from mild cognitive impairment to Alzheimer’s dementia in individuals with previous depression. Am J Psychiatry. 2018;175:232–41.

    PubMed  Google Scholar 

  221. Baazaoui N, Iqbal K. Prevention of amyloid-β and Tau pathologies, associated neurodegeneration, and cognitive deficit by early treatment with a neurotrophic compound. J Alzheimer’s Dis. 2017;58:215–30.

    CAS  Google Scholar 

  222. Baazaoui N, Iqbal K. Prevention of dendritic and synaptic deficits and cognitive impairment with a neurotrophic compound. Alzheimer’s Res Ther. 2017;9:45–45.

    Google Scholar 

  223. Kazim SF, Blanchard J, Dai CL, Tung YC, LaFerla FM, Iqbal IG, et al. Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer’s disease. Neurobiol Dis. 2014;71:110–30.

    CAS  PubMed  Google Scholar 

  224. Li B, Wanka L, Blanchard J, Liu F, Chohan MO, Iqbal K, et al. Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice. FEBS Lett. 2010;584:3359–65.

    CAS  PubMed  Google Scholar 

  225. James ML, Belichenko NP, Shuhendler AJ, Hoehne A, Andrews LE, Condon C, et al. [(18)F]GE-180 PET detects reduced microglia activation after LM11A-31 therapy in a mouse model of Alzheimer’s Disease. Theranostics. 2017;7:1422–36.

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Funding

This work was supported by the Key Laboratory of Alzheimer’s Disease of Zhejiang Province (ZJAD-2021004), the National Natural Science Foundation of China (82201576), Beijing Hospitals Authority Youth Programme (QML20210804) and Beijing Medical Research 2021-8 (YZ), and the National Natural Science Foundation of China (82230043; 82293642 and 82150710557) to WS. WS was the Canada Research Chair in Alzheimer’s Disease.

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Authors and Affiliations

  1. The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China

    Jing Yao, Zhe Wang, Weihong Song & Yun Zhang

  2. Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325000, Zhejiang, China

    Weihong Song

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  1. Jing Yao
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All authors were involved in literature search and writing of the article. WS supervised the project.

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The original online version of this article was revised: In this article, an incorrect table was inadvertently displayed as Table 2 and the captions for Figure 3 and Figure 4 were inadvertently swapped. The original article has been corrected.

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Yao, J., Wang, Z., Song, W. et al. Targeting NLRP3 inflammasome for neurodegenerative disorders. Mol Psychiatry 28, 4512–4527 (2023). https://doi.org/10.1038/s41380-023-02239-0

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