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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2016

Open Access 01-12-2016 | Research article

The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease

Authors: Marina Saresella, Francesca La Rosa, Federica Piancone, Martina Zoppis, Ivana Marventano, Elena Calabrese, Veronica Rainone, Raffaello Nemni, Roberta Mancuso, Mario Clerici

Published in: Molecular Neurodegeneration | Issue 1/2016

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Abstract

Background

Interleukin-1 beta (IL-1β) and its key regulator, the inflammasome, are suspected to play a role in the neuroinflammation observed in Alzheimer’s disease (AD); no conclusive data are nevertheless available in AD patients.

Results

mRNA for inflammasome components (NLRP1, NLRP3, PYCARD, caspase 1, 5 and 8) and downstream effectors (IL-1β, IL-18) was up-regulated in severe and MILD AD. Monocytes co-expressing NLRP3 with caspase 1 or caspase 8 were significantly increased in severe AD alone, whereas those co-expressing NLRP1 and NLRP3 with PYCARD were augmented in both severe and MILD AD. Activation of the NLRP1 and NLRP3 inflammasomes in AD was confirmed by confocal microscopy proteins co-localization and by the significantly higher amounts of the pro-inflammatory cytokines IL-1β and IL-18 being produced by monocytes. In MCI, the expression of NLRP3, but not the one of PYCARD or caspase 1 was increased, indicating that functional inflammasomes are not assembled in these individuals: this was confirmed by lack of co-localization and of proinflammatory cytokines production.

Conclusions

The activation of at least two different inflammasome complexes explains AD-associated neuroinflammation. Strategies targeting inflammasome activation could be useful in the therapy of AD.
Literature
1.
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;19:353–6.CrossRef
2.
3.
Jin C, Flavell RA. Molecular mechanism of NLRP3 inflammasome activation. J Clin Immunol. 2010;30(5):628–31.CrossRefPubMed
4.
5.
Gurung P, Anand PK, Malireddi RK, Vande Walle L, Van Opdenbosch N, Dillon CP, Weinlich R, Green DR, Lamkanfi M, Kanneganti TD. FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J Immunol. 2014;192(4):1835–46.
6.
7.
Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183(2):787–91.
8.
Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229–65.CrossRefPubMed
9.
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(3):319–25.CrossRefPubMed
10.
Martinon F, Agostini L, Meylan E, Tschopp J. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr Biol. 2004a;14(21):1929–34.
11.
Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell. 2004b;117(5):561–74.
12.
Kanneganti TD, Body-Malapel M, Amer A, Park JH, Whitfield J, Franchi L, Taraporewala ZF, Miller D, Patton JT, Inohara N, Núñez G. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem. 2006;281(48):36560–8.
13.
Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Dixit VM. Cryopyrin activates the inflammasomein response to toxins and ATP. Nature. 2006;440(7081):228–32.
14.
Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9(8):857–65.
15.
Bryant C, Fitzgerald KA. Molecular mechanisms involved in inflammasome activation. Trends Cell Biol. 2009;19(9):455–64.CrossRefPubMed
16.
Horvath GL, Schrum JE, De Nardo CM, Latz E. Intracellular sensing of microbes and danger signals by the inflammasomes. Immunol Rev. 2011;243(1):119–35.CrossRefPubMedPubMedCentral
17.
Wen H, Miao EA, Ting JP. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity. 2013;39(3):432–41.CrossRefPubMed
18.
19.
Rubartelli A. Redox control of NLRP3 inflammasome activation in health and disease. J Leukoc Biol. 2012;92(5):951–8.CrossRefPubMed
20.
Master SL. Specific inflammasomes in complex diseases. Clin Immunol. 2013;143:223–8.CrossRef
21.
22.
Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kauppinen A. Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer’s pathology. J Cell Mol Med. 2008;12(6A):2255–62.CrossRefPubMedPubMedCentral
23.
Masters SL, O’Neill LA. Disease-associated amyloid and misfolded protein aggregates activate the inflammasome. Trends Mol Med. 2011;17(5):276–82.CrossRefPubMed
24.
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493(7434):674–8.
25.
Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, van Bruggen R, Tschopp J. Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J Histochem Cytochem. 2007;55(5):443–52. PubMed PMID: 17164409, Epub 2006 Dec 12.
26.
Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol. 2014;14(7):463–77.CrossRefPubMed
27.
Heneka MT, Carson MJ, Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015a;14:388–405.
28.
Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer’s disease. Nat Immunol. 2015b;16:229–36.
29.
Tan MS, Yu JT, Jiang T, Zhu XC, Tan L. The NLRP3 inflammasome in Alzheimer’s disease. Mol Neurobiol. 2013;48(3):875–82.CrossRefPubMed
30.
Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Alberoni M, Nemni R, Clerici M. Increased activity of Th-17 and Th-9 lymphocytes and a skewing of the post-thymic differentiation pathway are seen in Alzheimer’s disease. Brain Behav Immun. 2011;25(3):539–47.
31.
Saresella M, Marventano I, Calabrese E, Piancone F, Rainone V, Gatti A, Alberoni M, Nemni R, Clerici M. A complex proinflammatory role for peripheral monocytes in Alzheimer’s disease. J Alzheimers Dis. 2014;38(2):403–13.
32.
Pontillo A, Catamo E, Arosio B, Mari D, Crovella S. NALP1/NLRP1 genetic variants are associated with Alzheimer disease. Alzheimer Dis Assoc Disord. 2012;26(3):277–81.CrossRefPubMed
33.
Darisipudi MN(1), Thomasova D, Mulay SR, Brech D, Noessner E, Liapis H, Anders HJ. Uromodulin triggers IL-1β-dependent innate immunity via the NLRP3 inflammasome. J Am Soc Nephrol. 2012;23(11):1783–9.
34.
Ni J, Wang P, Zhang J, Chen W, Gu L. Silencing of the P2X7 receptor enhances amyloid-b phagocytosis by microglia biochemical and biophysical research. Communications. 2013;434:363–9.
35.
36.
Pickering M, O’Connor JJ. Pro-inflammatory cytokines and their effects in the dentate gyrus. Prog Brain Res. 2007;163:339–54.CrossRefPubMed
37.
Murray CA, Lynch MA. Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci Off J Soc Neurosci. 1998;18(8):2974–81.
38.
Ojala J, Alafuzoff I, Herukka SK, van Groen T, Tanila H, Pirttila T. Expression of interleukin-18 is increased in the brains of Alzheimer’s disease patients. Neurobiol Aging. 2009;30(2):198–209.CrossRefPubMed
39.
Malaguarnera L, Motta M, Di Rosa M, Anzaldi M, Malaguarnera M. Interleukin-18 and transforming growth factor-beta 1 plasma levels in Alzheimer’s disease and vascular dementia. Neuropathology. 2006;26(4):307–12.CrossRefPubMed
40.
Bossù P, Ciaramella A, Salani F, Vanni D, Palladino I, Caltagirone C, Scapigliati G. Interleukin-18, from neuroinflammation to Alzheimer’s disease. Curr Pharm Des. 2010;16(38):4213–24.
41.
Salani F, Ciaramella A, Bizzoni F, Assogna F, Caltagirone C, Spalletta G, Bossù P. Increased expression of interleukin-18 receptor in blood cells of subjects with mild cognitive impairment and Alzheimer’s disease. Cytokine. 2013;61(2):360–3.
42.
Sutinen EM, Pirttilä T, Anderson G, Salminen A, Ojala JO. Pro-inflammatory interleukin-18 increases Alzheimer’s disease-associated amyloid-β production in human neuron-like cells. J Neuroinflammation. 2012;9:199.CrossRefPubMedPubMedCentral
43.
Chapuis J, Hot D, Hansmannel F, Kerdraon O, Ferreira S, Hubans C, Maurage CA, Huot L, Bensemain F, Laumet G, Ayral AM, Fievet N, Hauw JJ, DeKosky ST, Lemoine Y, Iwatsubo T, Wavrant-Devrièze F, Dartigues JF, Tzourio C, Buée L, Pasquier F, Berr C, Mann D, Lendon C, Alpérovitch A, Kamboh MI, Amouyel P, Lambert JC. Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer’s disease. Mol Psychiatry. 2009;14:1004–16.
44.
Fryer JD, Taylor JW, DeMattos RB, Bales KR, Paul SM, Parsadanian M, Holtzman DM. Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice. J Neurosci. 2003;23:7889–96.
45.
Lee DCY, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm. 2010;117:949–60.CrossRefPubMed
46.
Ali S, Mohs A, Thomas M, Klare J, Ross R, Schmitz ML, Martin MU. The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB-stimulated gene transcription. J Immunol. 2011;187:1609–16.
47.
Rezai-Zadeh K, Gate D, Town T. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease? J Neuroimmune Pharmacol. 2009;4:462–75.CrossRefPubMedPubMedCentral
48.
49.
Pan XD, Zhu YG, Lin N, Zhang J, Ye QY, Huang HP, Chen XC. Microglial phagocytosis induced by fibrillar b-amyloid is attenuated by oligomeric b-amyloid: implications for Alzheimer’s disease. Mol Neurodegener. 2011;6:45.
50.
Fowler BJ, Gelfand BD, Kim Y, Kerur NM, Tarallo V, Hirano Y, Amarnath S, Fowler DH, Radwan M, Young MT, Pittman K, Kubes P, Agarwal HK, Parang K, Hinton DR, Bastos-Carvalho A, Li S, Yasuma T, Mizutani T, Yasuma R, Wright C, Ambati J. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science. 2014;346:1000–3.
51.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s Disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Service Task Force on Alzheimer’s Disease. Neurology. 1984;34(7):939–44.CrossRefPubMed
52.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders DSM-IV-R. 1994.
53.
Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients for the clinicians. J Psychiat Res. 1975;12(3):189–98.CrossRefPubMed
54.
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for staging of dementia. Br J Psychiatry. 1982;140:566–72.CrossRefPubMed
55.
56.
Ligthart GJ, Corberand JX, Fournier C, Galanaud P, Hijmans W, Kennes B, Müller-Hermelink HK, Steinmann GG. Admission criteria for immunogerontological studies in man: the SENIEUR protocol. Mech Ageing Dev. 1984;28(1):47–55.
57.
Speciale L, Calabrese E, Saresella M, Tinelli C, Mariani C, Sanvito L, Longhi R, Ferrante P. Lymphocyte subset patterns and cytokines production in Alzheimer’s disease patients. Neurbiol Aging. 2007;28(8):1163–9.
58.
Delirezh N, Shojaeefar E, Parvin P, Asadi B. Comparison the effects of two monocyte isolation methods, plastic adherence and magnetic activated cell sorting methods, on phagocytic activity of generated dendritic cells. Cell J. 2013;15:218–23.PubMedPubMedCentral
59.
Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.CrossRefPubMed
60.
Dostert C, Pétrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science. 2008;320:674–7.CrossRefPubMedPubMedCentral
61.
Saeed AI, Sharov V, White J, Li J, Liang W, Bhagabati N, Braisted J, Klapa M, Currier T, Thiagarajan M, Sturn A, Snuffin M, Rezantsev A, Popov D, Ryltsov A,Kostukovich E, Borisovsky I, Liu Z, Vinsavich A, Trush V, Quackenbush J. TM4: a free, open-source system for microarray data management and analysis. Biotechniques. 2003;34:374-8.
62.
Bolte S, Cordelières FP. A guided tour into subcellular colocalization analysis in light microscopy. J Microsc. 2006;224:213-232.
63.
Manders EMM. Chromatic shift in multicolour confocal microscopy. J Microsc. 1997;185:321-28.
64.
French AP, Mills S, Swarup R, Bennet MJ, Pridmore TP. Colocalization of fluorescent markers in confocal microscope images of plant cells, Nat Protoc. 2008;4:619-28.
65.
Xiang Li, Zhang Y, Xia M, Gulbins E, Boini KM, Li PL. Activation of Nlrp3 Inflammasomes Enhances Macrophage Lipid-Deposition and Migration: Implicationof a Novel Role of Inflammasome in Atherogenesis. PLOS ONE. 2014;9(1):e87552.
Metadata
Title
The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease
Authors
Marina Saresella
Francesca La Rosa
Federica Piancone
Martina Zoppis
Ivana Marventano
Elena Calabrese
Veronica Rainone
Raffaello Nemni
Roberta Mancuso
Mario Clerici
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2016
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-016-0088-1

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