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01-03-2016 | Original Paper

Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes

Authors: Corinna Bliederhaeuser, Veselin Grozdanov, Anna Speidel, Lisa Zondler, Wolfgang P. Ruf, Hanna Bayer, Martin Kiechle, Marisa S. Feiler, Axel Freischmidt, David Brenner, Anke Witting, Bastian Hengerer, Marcus Fändrich, Albert C. Ludolph, Jochen H. Weishaupt, Frank Gillardon, Karin M. Danzer

Published in: Acta Neuropathologica | Issue 3/2016

Abstract

Extracellular alpha-synuclein (αsyn) oligomers, associated to exosomes or free, play an important role in the pathogenesis of Parkinson’s disease (PD). Increasing evidence suggests that these extracellular moieties activate microglia leading to enhanced neuronal damage. Despite extensive efforts on studying neuroinflammation in PD, little is known about the impact of age on microglial activation and phagocytosis, especially of extracellular αsyn oligomers. Here, we show that microglia isolated from adult mice, in contrast to microglia from young mice, display phagocytosis deficits of free and exosome-associated αsyn oligomers combined with enhanced TNFα secretion. In addition, we describe a dysregulation of monocyte subpopulations with age in mice and humans. Accordingly, human monocytes from elderly donors also show reduced phagocytic activity of extracellular αsyn. These findings suggest that these age-related alterations may contribute to an increased susceptibility to pathogens or abnormally folded proteins with age in neurodegenerative diseases.

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Alvarez-Erviti L, Seow Y, Schapira AH, Gardiner C, Sargent IL, Wood MJ et al (2011) Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis 42:360–367. doi:10.1016/j.nbd.2011.01.029 PubMedCentralCrossRefPubMed

Bellingham SA, Guo BB, Coleman BM, Hill AF (2012) Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front Physiol 3:124. doi:10.3389/fphys.2012.00124 PubMedCentralCrossRefPubMed

Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G et al (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143. doi:10.1038/nn.3599 PubMedCentralCrossRefPubMed

Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10:826–837. doi:10.1038/nri2873 PubMedCentralCrossRefPubMed

Chernyshev VS, Rachamadugu R, Tseng YH, Belnap DM, Jia Y, Branch KJ et al (2015) Size and shape characterization of hydrated and desiccated exosomes. Anal Bioanal Chem 407:3285–3301. doi:10.1007/s00216-015-8535-3 CrossRefPubMed

Cros J, Cagnard N, Woollard K, Patey N, Zhang SY, Senechal B et al (2010) Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33:375–386. doi:10.1016/j.immuni.2010.08.012 PubMedCentralCrossRefPubMed

Danzer KM, Haasen D, Karow AR, Moussaud S, Habeck M, Giese A et al (2007) Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci 27:9220–9232. doi:10.1523/JNEUROSCI.2617-07.2007 CrossRefPubMed

Danzer KM, Ruf WP, Putcha P, Joyner D, Hashimoto T, Glabe C et al (2011) Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity. FASEB J 25:326–336. doi:10.1096/fj.10-164624 PubMedCentralCrossRefPubMed

Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L et al (2012) Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 7:42. doi:10.1186/1750-1326-7-42 PubMedCentralCrossRefPubMed

10.

Dickson DW, Crystal HA, Mattiace LA, Masur DM, Blau AD, Davies P et al (1992) Identification of normal and pathological aging in prospectively studied nondemented elderly humans. Neurobiol Aging 13:179–189CrossRefPubMed

11.

Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH et al (2010) Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci 30:6838–6851. doi:10.1523/JNEUROSCI.5699-09.2010 PubMedCentralCrossRefPubMed

12.

Erwig LP, Henson PM (2007) Immunological consequences of apoptotic cell phagocytosis. Am J Pathol 171:2–8. doi:10.2353/ajpath.2007.070135 PubMedCentralCrossRefPubMed

13.

Esiri MM (2007) The interplay between inflammation and neurodegeneration in CNS disease. J Neuroimmunol 184:4–16. doi:10.1016/j.jneuroim.2006.11.013 CrossRefPubMed

14.

Eugenin EA, Eckardt D, Theis M, Willecke K, Bennett MV, Saez JC (2001) Microglia at brain stab wounds express connexin 43 and in vitro form functional gap junctions after treatment with interferon-gamma and tumor necrosis factor-alpha. Proc Natl Acad Sci USA 98:4190–4195. doi:10.1073/pnas.051634298 PubMedCentralCrossRefPubMed

15.

Fedoroff S, Richardson A (2001) Cultures of astroglia and microglia from primary cultures of mouse neopallium. Protocols for neural cell culture, 3rd edn. Humana Press, Totowa, pp 139–147CrossRef

16.

Feng D, Zhao WL, Ye YY, Bai XC, Liu RQ, Chang LF et al (2010) Cellular internalization of exosomes occurs through phagocytosis. Traffic 11:675–687. doi:10.1111/j.1600-0854.2010.01041.x CrossRefPubMed

17.

Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M et al (2004) Cells release prions in association with exosomes. Proc Natl Acad Sci USA 101:9683–9688. doi:10.1073/pnas.0308413101 PubMedCentralCrossRefPubMed

18.

Fischer HG, Reichmann G (2001) Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J Immunol 166:2717–2726CrossRefPubMed

19.

Fjorback AW, Varming K, Jensen PH (2007) Determination of alpha-synuclein concentration in human plasma using ELISA. Scand J Clin Lab Invest 67:431–435. doi:10.1080/00365510601161497 CrossRefPubMed

20.

Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F et al (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105. doi:10.1016/j.mad.2006.11.016 CrossRefPubMed

21.

Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH (2010) TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev 235:172–189. doi:10.1111/j.0105-2896.2010.00903.x PubMedCentralCrossRefPubMed

22.

Gao L, Brenner D, Llorens-Bobadilla E, Saiz-Castro G, Frank T, Wieghofer P et al (2015) Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice. J Exp Med 212:469–480. doi:10.1084/jem.20132423 PubMedCentralCrossRefPubMed

23.

Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20:269–287CrossRefPubMed

24.

Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82CrossRefPubMed

25.

Gillardon F, Schmid R, Draheim H (2012) Parkinson’s disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity. Neuroscience 208:41–48. doi:10.1016/j.neuroscience.2012.02.001 CrossRefPubMed

26.

Godbout JP, Chen J, Abraham J, Richwine AF, Berg BM, Kelley KW et al (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 19:1329–1331. doi:10.1096/fj.05-3776fje PubMed

27.

Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2:492–501. doi:10.1038/35081564 CrossRefPubMed

28.

Grozdanov V, Bliederhaeuser C, Ruf WP, Roth V, Fundel-Clemens K, Zondler L et al (2014) Inflammatory dysregulation of blood monocytes in Parkinson’s disease patients. Acta Neuropathol. doi:10.1007/s00401-014-1345-4 PubMedCentralPubMed

29.

Harms AS, Cao S, Rowse AL, Thome AD, Li X, Mangieri LR et al (2013) MHCII is required for alpha-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J Neurosci 33:9592–9600. doi:10.1523/jneurosci.5610-12.2013 PubMedCentralCrossRefPubMed

30.

Hasegawa T, Konno M, Baba T, Sugeno N, Kikuchi A, Kobayashi M et al (2011) The AAA-ATPase VPS4 regulates extracellular secretion and lysosomal targeting of alpha-synuclein. PLoS One 6:e29460. doi:10.1371/journal.pone.0029460 PubMedCentralCrossRefPubMed

31.

Huang YC, Feng ZP (2013) The good and bad of microglia/macrophages: new hope in stroke therapeutics. Acta Pharmacol Sin 34:6–7. doi:10.1038/aps.2012.178 PubMedCentralCrossRefPubMed

32.

Ito U, Nagasao J, Kawakami E, Oyanagi K (2007) Fate of disseminated dead neurons in the cortical ischemic penumbra: ultrastructure indicating a novel scavenger mechanism of microglia and astrocytes. Stroke 38:2577–2583. doi:10.1161/strokeaha.107.484394 CrossRefPubMed

33.

Kim YS, Joh TH (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med 38:333–347. doi:10.1038/emm.2006.40 CrossRefPubMed

34.

Klegeris A, McGeer EG, McGeer PL (2007) Therapeutic approaches to inflammation in neurodegenerative disease. Curr Opin Neurol 20:351–357. doi:10.1097/WCO.0b013e3280adc943 CrossRefPubMed

35.

Knott C, Stern G, Wilkin GP (2000) Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol Cell Neurosci 16:724–739. doi:10.1006/mcne.2000.0914 CrossRefPubMed

36.

Lee CK, Klopp RG, Weindruch R, Prolla TA (1999) Gene expression profile of aging and its retardation by caloric restriction. Science 285:1390–1393CrossRefPubMed

37.

Lee HJ, Suk JE, Bae EJ, Lee SJ (2008) Clearance and deposition of extracellular alpha-synuclein aggregates in microglia. Biochem Biophys Res Commun 372:423–428. doi:10.1016/j.bbrc.2008.05.045 CrossRefPubMed

38.

Lemke G, Rothlin CV (2008) Immunobiology of the TAM receptors. Nat Rev Immunol 8:327–336. doi:10.1038/nri2303 PubMedCentralCrossRefPubMed

39.

Long-Smith CM, Sullivan AM, Nolan YM (2009) The influence of microglia on the pathogenesis of Parkinson’s disease. Prog Neurobiol 89:277–287. doi:10.1016/j.pneurobio.2009.08.001 CrossRefPubMed

40.

Luo XG, Ding JQ, Chen SD (2010) Microglia in the aging brain: relevance to neurodegeneration. Mol Neurodegener 5:12. doi:10.1186/1750-1326-5-12 PubMedCentralCrossRefPubMed

41.

Maher FO, Nolan Y, Lynch MA (2005) Downregulation of IL-4-induced signalling in hippocampus contributes to deficits in LTP in the aged rat. Neurobiol Aging 26:717–728. doi:10.1016/j.neurobiolaging.2004.07.002 CrossRefPubMed

42.

McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291CrossRefPubMed

43.

Mirza B, Hadberg H, Thomsen P, Moos T (2000) The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson’s disease. Neuroscience 95:425–432CrossRefPubMed

44.

Moussaud S, Draheim HJ (2010) A new method to isolate microglia from adult mice and culture them for an extended period of time. J Neurosci Methods 187:243–253. doi:10.1016/j.jneumeth.2010.01.017 CrossRefPubMed

45.

Moussaud S, Malany S, Mehta A, Vasile S, Smith LH, McLean PJ (2015) Targeting alpha-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies. Expert Opin Ther Targets 19:589–603. doi:10.1517/14728222.2015.1009448 CrossRefPubMed

46.

Napoli I, Neumann H (2009) Microglial clearance function in health and disease. Neuroscience 158:1030–1038. doi:10.1016/j.neuroscience.2008.06.046 CrossRefPubMed

47.

Neumann H, Kotter MR, Franklin RJ (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132:288–295. doi:10.1093/brain/awn109 PubMedCentralCrossRefPubMed

48.

Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318. doi:10.1126/science.1110647 CrossRefPubMed

49.

Norden DM, Godbout JP (2013) Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39:19–34. doi:10.1111/j.1365-2990.2012.01306.x PubMedCentralCrossRefPubMed

50.

Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F et al (2008) Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS One 3:e1867. doi:10.1371/journal.pone.0001867 PubMedCentralCrossRefPubMed

51.

Phinney AL, Andringa G, Bol JG, Wolters E, van Muiswinkel FL, van Dam AM et al (2006) Enhanced sensitivity of dopaminergic neurons to rotenone-induced toxicity with aging. Parkinsonism Relat Disord 12:228–238. doi:10.1016/j.parkreldis.2005.12.002 CrossRefPubMed

52.

Prokop S, Miller KR, Heppner FL (2013) Microglia actions in Alzheimer’s disease. Acta Neuropathol 126:461–477CrossRefPubMed

53.

Remy I, Michnick SW (2006) A highly sensitive protein-protein interaction assay based on Gaussia luciferase. Nat Methods 3:977–979. doi:10.1038/nmeth979 CrossRefPubMed

54.

Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A (2007) Neuroinflammation in Alzheimer’s disease and Parkinson’s disease: are microglia pathogenic in either disorder? Int Rev Neurobiol 82:235–246. doi:10.1016/s0074-7742(07)82012-5 CrossRefPubMed

55.

Sawada H, Hishida R, Hirata Y, Ono K, Suzuki H, Muramatsu S et al (2007) Activated microglia affect the nigro-striatal dopamine neurons differently in neonatal and aged mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurosci Res 85:1752–1761. doi:10.1002/jnr.21241 CrossRefPubMed

56.

Scott RS, McMahon EJ, Pop SM, Reap EA, Caricchio R, Cohen PL et al (2001) Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411:207–211. doi:10.1038/35075603 CrossRefPubMed

57.

Shi M, Liu C, Cook TJ, Bullock KM, Zhao Y, Ginghina C et al (2014) Plasma exosomal alpha-synuclein is likely CNS-derived and increased in Parkinson’s disease. Acta Neuropathol 128:639–650. doi:10.1007/s00401-014-1314-y PubMedCentralCrossRefPubMed

58.

Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS et al (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:483–495. doi:10.1016/j.stem.2010.08.014 PubMedCentralCrossRefPubMed

59.

Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ (2010) HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 28:367–388. doi:10.1146/annurev.immunol.021908.132603 CrossRefPubMed

60.

Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci USA 95:6469–6473PubMedCentralCrossRefPubMed

61.

Teismann P, Schulz JB (2004) Cellular pathology of Parkinson’s disease: astrocytes, microglia and inflammation. Cell Tissue Res 318:149–161. doi:10.1007/s00441-004-0944-0 CrossRefPubMed

62.

Thery C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol Chapter 3: Unit 3 22 doi 10.1002/0471143030.cb0322s30

63.

von Bernhardi R, Tichauer JE, Eugenin J (2010) Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem 112:1099–1114. doi:10.1111/j.1471-4159.2009.06537.x CrossRef

64.

Yamada T, McGeer PL, McGeer EG (1992) Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. Acta Neuropathol 84:100–104CrossRefPubMed

65.

Ye SM, Johnson RW (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9:183–192. doi:10.1159/000049025 CrossRefPubMed

66.

Yona S, Jung S (2010) Monocytes: subsets, origins, fates and functions. Curr Opin Hematol 17:53–59. doi:10.1097/MOH.0b013e3283324f80 CrossRefPubMed

67.

Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML et al (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19:533–542. doi:10.1096/fj.04-2751com CrossRefPubMed

68.

Zhou X, He X, Ren Y (2014) Function of microglia and macrophages in secondary damage after spinal cord injury. Neural Regen Res 9:1787–1795. doi:10.4103/1673-5374.143423 PubMedCentralCrossRefPubMed

Title: Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes
Authors: Corinna Bliederhaeuser
Veselin Grozdanov
Anna Speidel
Lisa Zondler
Wolfgang P. Ruf
Hanna Bayer
Martin Kiechle
Marisa S. Feiler
Axel Freischmidt
David Brenner
Anke Witting
Bastian Hengerer
Marcus Fändrich
Albert C. Ludolph
Jochen H. Weishaupt
Frank Gillardon
Karin M. Danzer
Publication date: 01-03-2016
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 3/2016
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1504-2

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Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes

Abstract

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