Abstract
Neuronal dysfunction and loss are thought to be one of the causes of cognitive impairment in Alzheimer's disease (AD), but the specific mechanism of neuronal loss in the pathogenesis of AD remains controversial. This study explored the role of NLRP3 inflammasome-induced neuronal pyroptosis in neuronal loss of AD, and pioneered the use of NLRP3 inhibitor MCC950 to intervene in the treatment of senescence-accelerated mouse prone 8 (SAMP8) mice. In vitro, human primary neurons (HPNs) pretreated with MCC950 were stimulated with amyloid-β1–42 (Aβ1–42), and it was found that MCC950 significantly reduced the neurotoxicity of Aβ1–42 by inhibiting neuronal pyroptosis. In vivo, SAMP8 mice were randomly divided into vehicle-treated group and MCC950-treated group, and it was found that MCC950 also played a positive role in treatment. The intervention of MCC950 improved the spatial memory ability and brain histological morphology of SAMP8 mice, and reduced the deposition of amyloid-β in the brain. Furthermore, MCC950 was found to inhibit the overexpressions of NLRP3, caspase-1, and GSDMD, which were the response factors of pyroptosis in SAMP8 mouse neurons, by immunofluorescence staining. In this study, we found that neuronal pyroptosis induced by the NLRP3/caspase-1/GSDMD axis was an important factor in neuronal loss of AD, and revealed that MCC950 might be a potential AD therapeutic agent.
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Abel S, Baird SK (2018) Honey is cytotoxic towards prostate cancer cells but interacts with the MTT reagent: considerations for the choice of cell viability assay. Food Chem 241:70–78. https://doi.org/10.1016/j.foodchem.2017.08.083
Alvarez-García O, Vega-Naredo I, Sierra V, Caballero B, Tomás-Zapico C, Camins A, García JJ, Pallàs M, Coto-Montes A (2006) Elevated oxidative stress in the brain of senescence-accelerated mice at 5 months of age. Biogerontology 7(1):43–52. https://doi.org/10.1007/s10522-005-6041-2
Aminzadeh M, Roghani M, Sarfallah A, Riazi GH (2018) TRPM2 dependence of ROS-induced NLRP3 activation in Alzheimer's disease. Int Immunopharmacol 54:78–85. https://doi.org/10.1016/j.intimp.2017.10.024
Boucher D, Monteleone M, Coll RC, Chen KW, Ross CM, Teo JL, Gomez GA, Holley CL, Bierschenk D, Stacey KJ, Yap AS, Bezbradica JS, Schroder K (2018) Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity. J Exp Med 215(3):827–840. https://doi.org/10.1084/jem.20172222
Butterfield DA, Poon HF (2005) The senescence-accelerated prone mouse (SAMP8): a model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer's disease. Exp Gerontol 40(10):774–783. https://doi.org/10.1016/j.exger.2005.05.007
Caccamo A, Magri A, Medina DX, Wisely EV, Lopez-Aranda MF, Silva AJ, Oddo S (2013) mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies. Aging Cell 12(3):370–380. https://doi.org/10.1111/acel.12057
Canter RG, Penney J, Tsai L (2016) The road to restoring neural circuits for the treatment of Alzheimer's disease. Nature 539(7628):187–196. https://doi.org/10.1038/nature20412
Canudas AM, Gutierrez-Cuesta J, Rodríguez MI, Acuña-Castroviejo D, Sureda FX, Camins A, Pallàs M (2005) Hyperphosphorylation of microtubule-associated protein tau in senescence-accelerated mouse (SAM). Mech Ageing Dev 126(12):1300–1304. https://doi.org/10.1016/j.mad.2005.07.008
Chang S, Guo X, Li G, Zhang X, Li J, Jia Y, Nie K (2019) Acupuncture promotes expression of Hsp84/86 and delays brain ageing in SAMP8 mice. Acupunct Med. https://doi.org/10.1136/acupmed-2017-011577
Chavoshinezhad S, Mohseni Kouchesfahani H, Ahmadiani A, Dargahi L (2019) Interferon beta ameliorates cognitive dysfunction in a rat model of Alzheimer's disease: modulation of hippocampal neurogenesis and apoptosis as underlying mechanism. Progress Neuro-Psychopharmacol Biol Psychiatry 94:109661. https://doi.org/10.1016/j.pnpbp.2019.109661
Ciancio G, Pollack A, Taupier MA, Block NL, Irvin GL (1988) Measurement of cell-cycle phase-specific cell death using Hoechst 33342 and propidium iodide: preservation by ethanol fixation. J Histochem Cytochem 36(9):1147–1152. https://doi.org/10.1177/36.9.2457047
Coll RC, Robertson AAB, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A, Croker DE, Butler MS, Haneklaus M, Sutton CE, Núñez G, Latz E, Kastner DL, Mills KHG, Masters SL, Schroder K, Cooper MA, O'Neill LAJ (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 21(3):248–255. https://doi.org/10.1038/nm.3806
Currais A, Huang L, Goldberg J, Petrascheck M, Ates G, Pinto-Duarte A, Shokhirev MN, Schubert D, Maher P (2019) Elevating acetyl-CoA levels reduces aspects of brain aging. eLife. https://doi.org/10.7554/eLife.47866
Daniels MJD, Rivers-Auty J, Schilling T, Spencer NG, Watremez W, Fasolino V, Booth SJ, White CS, Baldwin AG, Freeman S, Wong R, Latta C, Yu S, Jackson J, Fischer N, Koziel V, Pillot T, Bagnall J, Allan SM, Paszek P, Galea J, Harte MK, Eder C, Lawrence CB, Brough D (2016) Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nat Commun. https://doi.org/10.1038/ncomms12504
Del VJ, Duran-Vilaregut J, Manich G, Casadesús G, Smith MA, Camins A, Pallàs M, Pelegrí C, Vilaplana J (2010) Early amyloid accumulation in the hippocampus of SAMP8 mice. J Alzheimers Dis 19(4):1303–1315. https://doi.org/10.3233/JAD-2010-1321
Del VJ, Bayod S, Camins A, Beas-Zárate C, Velázquez-Zamora DA, González-Burgos I, Pallàs M (2012) Dendritic spine abnormalities in hippocampal CA1 pyramidal neurons underlying memory deficits in the SAMP8 mouse model of Alzheimer's disease. J Alzheimers Dis 32(1):233–240. https://doi.org/10.3233/JAD-2012-120718
Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang D, Shao F (2016a) Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535(7610):111–116. https://doi.org/10.1038/nature18590
Eimer WA, Vassar R (2013) Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ 42 accumulation and caspase-3 activation. Mol Neurodegener 8(1):2
Gao S, Lin J, Wang T, Shen Y, Li Y, Yang W, Zhou K, Hu H (2019) Qingxin kaiqiao fang ameliorates memory impairment and inhibits apoptosis in APP/PS1 double transgenic mice through the MAPK pathway. 13:459–475. https://doi.org/10.2147/DDDT.S188505
Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol 9(8):857–865. https://doi.org/10.1038/ni.1636
Han GY, Li CY, Shi HB, Wang JP, Su KM, Yin XL, Yin SK (2015) Riluzole is a promising pharmacological inhibitor of bilirubin-induced excitotoxicity in the ventral cochlear nucleus. CNS Neurosci Ther 21(3):262–270. https://doi.org/10.1111/cns.12355
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297(5580):353–356. https://doi.org/10.1126/science.1072994
He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J (2015) Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res 25(12):1285–1298. https://doi.org/10.1038/cr.2015.139
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng T, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2012) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493(7434):674–678. https://doi.org/10.1038/nature11729
Heneka MT, Kummer MP, Latz E (2014) Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14(7):463–477. https://doi.org/10.1038/nri3705
Heneka MT, McManus RM, Latz E (2018) Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci 19(10):610–621. https://doi.org/10.1038/s41583-018-0055-7
Ismael S, Nasoohi S, Ishrat T (2018) MCC950, the selective inhibitor of nucleotide oligomerization domain-like receptor protein-3 inflammasome, protects mice against traumatic brain injury. J Neurotraum 35(11):1294–1303. https://doi.org/10.1089/neu.2017.5344
Jaroudi W, Garami J, Garrido S, Hornberger M, Keri S, Moustafa AA (2017) Factors underlying cognitive decline in old age and Alzheimer's disease: the role of the hippocampus. Rev Neurosci 28(7):705–714. https://doi.org/10.1515/revneuro-2016-0086
Krishna K, Behnisch T, Sajikumar S (2016) Inhibition of histone deacetylase 3 restores amyloid-β oligomer-induced plasticity deficit in hippocampal CA1 pyramidal neurons. J Alzheimers Dis 51(3):783–791. https://doi.org/10.3233/JAD-150838
Lazarov O, Mattson MP, Peterson DA, Pimplikar SW, van Praag H (2010) When neurogenesis encounters aging and disease. Trends Neurosci 33(12):569–579. https://doi.org/10.1016/j.tins.2010.09.003
Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J (2016) Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535(7610):153–158. https://doi.org/10.1038/nature18629
Lv LL, Liu B, Liu J, Li LS, Jin F, Xu YY, Wu Q, Liu J, Shi JS (2020) Dendrobium nobile lindl alkaloids ameliorate cognitive dysfunction in senescence accelerated SAMP8 mice by decreasing amyloid-β aggregation and enhancing autophagy activity. J Alzheimers Dis. https://doi.org/10.3233/JAD-200308
Man SM, Kanneganti T (2015) Gasdermin D: the long-awaited executioner of pyroptosis. Cell Res 25(11):1183–1184. https://doi.org/10.1038/cr.2015.124
Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Trojanowski JQ, Vinters HV, Hyman BT (2012) National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol 123(1):1–11. https://doi.org/10.1007/s00401-011-0910-3
Nisbet RM, Van der Jeugd A, Leinenga G, Evans HT, Janowicz PW, Götz J (2017) Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain 140(5):1220–1230. https://doi.org/10.1093/brain/awx052
Nobili A, Latagliata EC, Viscomi MT, Cavallucci V, Cutuli D, Giacovazzo G, Krashia P, Rizzo FR, Marino R, Federici M, De Bartolo P, Aversa D, Dell'Acqua MC, Cordella A, Sancandi M, Keller F, Petrosini L, Puglisi-Allegra S, Mercuri NB, Coccurello R, Berretta N, D'Amelio M (2017) Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease. Nat Commun 8:14727. https://doi.org/10.1038/ncomms14727
Pereira CF, Santos AE, Moreira PI, Pereira AC, Sousa FJ, Cardoso SM, Cruz MT (2019) Is Alzheimer's disease an inflammasomopathy? Ageing Res Rev 56:100966. https://doi.org/10.1016/j.arr.2019.100966
Perregaux DG, McNiff P, Laliberte R, Hawryluk N, Peurano H, Stam E, Eggler J, Griffiths R, Dombroski MA, Gabel CA (2001) Identification and characterization of a novel class of interleukin-1 post-translational processing inhibitors. J Pharmacol Exp Ther 299(1):187–197
Ren H, Kong Y, Liu Z, Zang D, Yang X, Wood K, Li M, Liu Q (2018) Selective NLRP3 (Pyrin Domain-Containing Protein 3) inflammasome inhibitor reduces brain injury after intracerebral hemorrhage. Stroke 49(1):184–192. https://doi.org/10.1161/STROKEAHA.117.018904
Sanchez-Mejias E, Nuñez-Diaz C, Sanchez-Varo R, Gomez-Arboledas A, Garcia-Leon JA, Fernandez-Valenzuela JJ, Mejias-Ortega M, Trujillo-Estrada L, Baglietto-Vargas D, Moreno-Gonzalez I, Davila JC, Vitorica J, Gutierrez A (2019) Distinct disease-sensitive GABAergic neurons in the perirhinal cortex of Alzheimer's mice and patients. Brain Pathol. https://doi.org/10.1111/bpa.12785
Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, Rainone V, Nemni R, Mancuso R, Clerici M (2016) The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegener. https://doi.org/10.1186/s13024-016-0088-1
Schroder K, Tschopp J (2010) The inflammasomes. Cell 140(6):821–832. https://doi.org/10.1016/j.cell.2010.01.040
Selkoe DJ (2002) Alzheimer's disease is a synaptic failure. Science 298(5594):789–791. https://doi.org/10.1126/science.1074069
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526(7575):660–665. https://doi.org/10.1038/nature15514
Shi J, Gao W, Shao F (2017) Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci 42(4):245–254. https://doi.org/10.1016/j.tibs.2016.10.004
Sun E (2008) Cell death recognition model for the immune system. Med Hypotheses 70(3):585–596. https://doi.org/10.1016/j.mehy.2007.05.049
Sun EW, Shi YF (2001) Apoptosis: the quiet death silences the immune system. Pharmacol Therapeut 92(2):135–145. https://doi.org/10.1016/S0163-7258(01)00164-4
Tanaka H, Homma H, Fujita K, Kondo K, Yamada S, Jin X, Waragai M, Ohtomo G, Iwata A, Tagawa K, Atsuta N, Katsuno M, Tomita N, Furukawa K, Saito Y, Saito T, Ichise A, Shibata S, Arai H, Saido T, Sudol M, Muramatsu S, Okano H, Mufson EJ, Sobue G, Murayama S, Okazawa H (2020) YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology. Nat Commun. https://doi.org/10.1038/s41467-020-14353-6
Tanisawa K, Mikami E, Fuku N, Honda Y, Honda S, Ohsawa I, Ito M, Endo S, Ihara K, Ohno K, Kishimoto Y, Ishigami A, Maruyama N, Sawabe M, Iseki H, Okazaki Y, Hasegawa-Ishii S, Takei S, Shimada A, Hosokawa M, Mori M, Higuchi K, Takeda T, Higuchi M, Tanaka M (2013) Exome sequencing of senescence-accelerated mice (SAM) reveals deleterious mutations in degenerative disease-causing genes. BMC Genomics 14:248. https://doi.org/10.1186/1471-2164-14-248
Tucey TM, Verma-Gaur J, Nguyen J, Hewitt VL, Lo TL, Shingu-Vazquez M, Robertson AA, Hill JR, Pettolino FA, Beddoe T, Cooper MA, Naderer T, Traven A (2016) The endoplasmic reticulum-mitochondrion tether ERMES orchestrates fungal immune evasion, illuminating inflammasome responses to hyphal signals. Msphere 1:3. https://doi.org/10.1128/mSphere.00074-16
van der Heijden T, Kritikou E, Venema W, van Duijn J, van Santbrink PJ, Slütter B, Foks AC, Bot I, Kuiper J (2017) NLRP3 inflammasome inhibition by MCC950 reduces atherosclerotic lesion development in apolipoprotein E-deficient mice-brief report. Arterioscler Thromb Vasc Biol 37(8):1457–1461. https://doi.org/10.1161/ATVBAHA.117.309575
Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1(2):848–858. https://doi.org/10.1038/nprot.2006.116
Wang Y, Buggia-Prevot V, Zavorka ME, Bleackley RC, MacDonald RG, Thinakaran G, Kar S (2015) Overexpression of the insulin-like growth factor II receptor increases beta-amyloid production and affects cell viability. Mol Cell Biol 35(14):2368–2384. https://doi.org/10.1128/MCB.01338-14
White CS, Lawrence CB, Brough D, Rivers-Auty J (2017) Inflammasomes as therapeutic targets for Alzheimer's disease. Brain Pathol 27(2):223–234. https://doi.org/10.1111/bpa.12478
Wilcock DM, Gharkholonarehe N, Van Nostrand WE, Davis J, Vitek MP, Colton CA (2009) Amyloid reduction by amyloid-vaccination also reduces mouse tau pathology and protects from neuron loss in two mouse models of Alzheimer's disease. J Neurosci 29(25):7957–7965. https://doi.org/10.1523/JNEUROSCI.1339-09.2009
Yang F, He Y, Zhai Z, Sun E (2019) Programmed cell death pathways in the pathogenesis of systemic lupus erythematosus. J Immunol Res 2019:1–13. https://doi.org/10.1155/2019/3638562
Ye X, Shen T, Hu J, Zhang L, Zhang Y, Bao L, Cui C, Jin G, Zan K, Zhang Z, Yang X, Shi H, Zu J, Yu M, Song C, Wang Y, Qi S, Cui G (2017) Purinergic 2X7 receptor/NLRP3 pathway triggers neuronal apoptosis after ischemic stroke in the mouse. Exp Neurol 292:46–55. https://doi.org/10.1016/j.expneurol.2017.03.002
Zhang Y, Lv X, Hu Z, Ye X, Zheng X, Ding Y, Xie P, Liu Q (2017) Protection of Mcc950 against high-glucose-induced human retinal endothelial cell dysfunction. Cell Death Disease 8(7):e2941. https://doi.org/10.1038/cddis.2017.308
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This work was supported by Grants from National Natural Science Foundation of China (Grant Nos. 81671623, 81873880, 81501417), and Medical Scientific Research Foundation of Guangdong Province (No. A2017296).
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JL: investigation, writing–original draft preparation; LZ: methodology, writing–original draft preparation; XL: data curation, software; JL: investigation, methodology; YH and ES: conceptualization, supervision, writing-reviewing and editing.
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Li, J., Zhuang, L., Luo, X. et al. Protection of MCC950 against Alzheimer's disease via inhibiting neuronal pyroptosis in SAMP8 mice. Exp Brain Res 238, 2603–2614 (2020). https://doi.org/10.1007/s00221-020-05916-6
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DOI: https://doi.org/10.1007/s00221-020-05916-6