Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture
2.2. Western Blotting
2.3. Detection of α-Synuclein Tetramers and Aggregates and Ferriductase Assay
2.4. Iron Assay
2.5. Reactive Oxygen Species Assay
2.6. Cytokine Quantitation
2.7. Promoter Assays
2.8. Proliferation Assay
2.9. Toxicity Assay
2.10. Statistics
3. Results
3.1. Generation and Characterisation of a Senescent Phenotype in Microglia
3.2. Proliferation and Cell Death
3.3. Altered Protein Expression in Iron-Fed Microglia
3.4. Reactive Oxygen Species Production
3.5. Cytokine Expression
3.6. Conditioned Medium from Iron-Fed Microglia Caused Increased α-Synuclein Expression
3.7. SNCA Promoter Activity Is Increased by Conditioned Medium from Iron-Fed Microglia
3.8. Neutralisation of Cytokines Released from Iron-Fed Microglia Blocks Increased α-Synuclein Expression
3.9. Increased α-Synuclein Expression Induced by Iron-Fed Microglia Was Mediated by the NF-κB Pathway
3.10. Conditioned Medium from Iron-Fed Microglia Caused a Decrease in α-Synuclein Activity
3.11. Aggregation of α-Synuclein
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
- Lindsay, J.; Laurin, D.; Verreault, R.; Hebert, R.; Helliwell, B.; Hill, G.B.; McDowell, I. Risk factors for Alzheimer’s disease: A prospective analysis from the canadian study of health and aging. Am. J. Epidemiol. 2002, 156, 445–453. [Google Scholar] [CrossRef] [PubMed]
- Wolf, S.A.; Boddeke, H.W.; Kettenmann, H. Microglia in physiology and disease. Annu. Rev. Physiol. 2017, 79, 619–643. [Google Scholar] [CrossRef] [PubMed]
- Aloisi, F. Immune function of microglia. Glia 2001, 36, 165–179. [Google Scholar] [CrossRef] [PubMed]
- Streit, W.J. Microglial senescence: Does the brain’s immune system have an expiration date? Trends Neurosci. 2006, 29, 506–510. [Google Scholar] [CrossRef] [PubMed]
- Streit, W.J.; Braak, H.; Xue, Q.S.; Bechmann, I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol. 2009, 118, 475–485. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Njie, E.G.; Boelen, E.; Stassen, F.R.; Steinbusch, H.W.; Borchelt, D.R.; Streit, W.J. Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol. Aging 2012, 33, 195.e1–195.e12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Solito, E.; Sastre, M. Microglia function in Alzheimer’s disease. Front. Pharmacol. 2012, 3, 14. [Google Scholar] [CrossRef] [PubMed]
- Luo, X.G.; Ding, J.Q.; Chen, S.D. Microglia in the aging brain: Relevance to neurodegeneration. Mol. Neurodegener. 2010, 5, 12. [Google Scholar] [CrossRef] [PubMed]
- Lopes, K.O.; Sparks, D.L.; Streit, W.J. Microglial dystrophy in the aged and Alzheimer’s disease brain is associated with ferritin immunoreactivity. Glia 2008, 56, 1048–1060. [Google Scholar] [CrossRef] [PubMed]
- Simmons, D.A.; Casale, M.; Alcon, B.; Pham, N.; Narayan, N.; Lynch, G. Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington’s disease. Glia 2007, 55, 1074–1084. [Google Scholar] [CrossRef] [PubMed]
- Zecca, L.; Gallorini, M.; Schunemann, V.; Trautwein, A.X.; Gerlach, M.; Riederer, P.; Vezzoni, P.; Tampellini, D. Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages: Consequences for iron storage and neurodegenerative processes. J. Neurochem. 2001, 76, 1766–1773. [Google Scholar] [CrossRef] [PubMed]
- Chen, Z.; Trapp, B.D. Microglia and neuroprotection. J. Neurochem. 2016, 136, 10–17. [Google Scholar] [CrossRef] [PubMed]
- Streit, W.J.; Xue, Q.S.; Tischer, J.; Bechmann, I. Microglial pathology. Acta Neuropathol. Commun. 2014, 2, 142. [Google Scholar] [CrossRef] [PubMed]
- Prokop, S.; Miller, K.R.; Heppner, F.L. Microglia actions in Alzheimer’s disease. Acta Neuropathol. 2013, 126, 461–477. [Google Scholar] [CrossRef] [PubMed]
- Spillantini, M.G.; Crowther, R.A.; Jakes, R.; Hasegawa, M.; Goedert, M. α-synuclein in filamentous inclusions of lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc. Natl. Acad. Sci. USA 1998, 95, 6469–6473. [Google Scholar] [CrossRef] [PubMed]
- Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.; Trojanowski, J.Q.; Jakes, R.; Goedert, M. α-synuclein in lewy bodies. Nature 1997, 388, 839–840. [Google Scholar] [CrossRef] [PubMed]
- Jakes, R.; Spillantini, M.G.; Goedert, M. Identification of two distinct synucleins from human brain. FEBS Lett. 1994, 345, 27–32. [Google Scholar] [CrossRef] [Green Version]
- Ueda, K.; Fukushima, H.; Masliah, E.; Xia, Y.; Iwai, A.; Yoshimoto, M.; Otero, D.A.; Kondo, J.; Ihara, Y.; Saitoh, T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 1993, 90, 11282–11286. [Google Scholar] [CrossRef] [PubMed]
- Masliah, E.; Iwai, A.; Mallory, M.; Ueda, K.; Saitoh, T. Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer’s disease. Am. J. Pathol. 1996, 148, 201–210. [Google Scholar] [PubMed]
- Hayashita-Kinoh, H.; Yamada, M.; Yokota, T.; Mizuno, Y.; Mochizuki, H. Down-regulation of α-synuclein expression can rescue dopaminergic cells from cell death in the substantia nigra of Parkinson’s disease rat model. Biochem. Biophys. Res. Commun. 2006, 341, 1088–1095. [Google Scholar] [CrossRef] [PubMed]
- McGeer, P.L.; McGeer, E.G. Glial reactions in Parkinson’s disease. Mov. Disord. 2008, 23, 474–483. [Google Scholar] [CrossRef] [PubMed]
- Tanaka, S.; Ishii, A.; Ohtaki, H.; Shioda, S.; Yoshida, T.; Numazawa, S. Activation of microglia induces symptoms of Parkinson’s disease in wild-type, but not in IL-1 knockout mice. J. Neuroinflamm. 2013, 10, 907. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Verina, T.; Kiihl, S.F.; Schneider, J.S.; Guilarte, T.R. Manganese exposure induces microglia activation and dystrophy in the substantia nigra of non-human primates. Neurotoxicology 2011, 32, 215–226. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Streit, W.J.; Xue, Q.S. Microglia in dementia with lewy bodies. Brain Behav. Immun. 2016, 55, 191–201. [Google Scholar] [CrossRef] [PubMed]
- Song, I.U.; Cho, H.J.; Kim, J.S.; Park, I.S.; Lee, K.S. Serum hs-CRP levels are increased in de Novo Parkinson’s disease independently from age of onset. Eur. Neurol. 2014, 72, 285–289. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Moualla, D.; Wright, J.A.; Brown, D.R. Copper binding regulates intracellular α-synuclein localisation, aggregation and toxicity. J. Neurochem. 2010, 113, 704–714. [Google Scholar] [CrossRef] [PubMed]
- Brown, D.R.; Schmidt, B.; Kretzschmar, H.A. A neurotoxic prion protein fragment enhances proliferation of microglia but not astrocytes in culture. Glia 1996, 18, 59–67. [Google Scholar] [CrossRef]
- Saura, J.; Tusell, J.M.; Serratosa, J. High-yield isolation of murine microglia by mild trypsinization. Glia 2003, 44, 183–189. [Google Scholar] [CrossRef] [PubMed]
- McDowall, J.S.; Ntai, I.; Hake, J.; Whitley, P.R.; Mason, J.M.; Pudney, C.R.; Brown, D.R. Steady-state kinetics of α-synuclein ferrireductase activity identifies the catalytically competent species. Biochemistry 2017, 56, 2497–2505. [Google Scholar] [CrossRef] [PubMed]
- Uy, B.; McGlashan, S.R.; Shaikh, S.B. Measurement of reactive oxygen species in the culture media using Acridan Lumigen PS-3 assay. J. Biomol. Tech. 2011, 22, 95–107. [Google Scholar] [PubMed]
- Wright, J.A.; McHugh, P.C.; Pan, S.; Cunningham, A.; Brown, D.R. Counter-regulation of alpha- and beta-synuclein expression at the transcriptional level. Mol. Cell. Neurosci. 2013, 57, 33–41. [Google Scholar] [CrossRef] [PubMed]
- Henle, E.S.; Linn, S. Formation, prevention, and repair of DNA damage by Iron/Hydrogen peroxide. J. Biol. Chem. 1997, 272, 19095–19098. [Google Scholar] [CrossRef] [PubMed]
- Schilling, T.; Eder, C. Microglial K+ channel expression in young adult and aged mice. Glia 2015, 63, 664–672. [Google Scholar] [CrossRef] [PubMed]
- Bennett, B.L.; Sasaki, D.T.; Murray, B.W.; O’Leary, E.C.; Sakata, S.T.; Xu, W.; Leisten, J.C.; Motiwala, A.; Pierce, S.; Satoh, Y.; et al. Sp600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. USA 2001, 98, 13681–13686. [Google Scholar] [CrossRef] [PubMed]
- Schepetkin, I.A.; Kirpotina, L.N.; Khlebnikov, A.I.; Hanks, T.S.; Kochetkova, I.; Pascual, D.W.; Jutila, M.A.; Quinn, M.T. Identification and characterization of a novel class of c-Jun N-terminal kinase inhibitors. Mol. Pharmacol. 2012, 81, 832–845. [Google Scholar] [CrossRef] [PubMed]
- Heynekamp, J.J.; Weber, W.M.; Hunsaker, L.A.; Gonzales, A.M.; Orlando, R.A.; Deck, L.M.; Jagt, D.L. Substituted trans-stilbenes, including analogues of the natural product resveratrol, inhibit the human tumor necrosis factor alpha-induced activation of transcription factor nuclear factor kappaB. J. Med. Chem. 2006, 49, 7182–7189. [Google Scholar] [CrossRef] [PubMed]
- Davies, P.; Moualla, D.; Brown, D.R. Alpha-synuclein is a cellular ferrireductase. PLoS ONE 2011, 6, e15814. [Google Scholar] [CrossRef]
- McDowall, J.S.; Ntai, I.; Honeychurch, K.C.; Hart, J.P.; Colin, P.; Schneider, B.L.; Brown, D.R. Alpha-synuclein ferrireductase activity is detectible in vivo, is altered in Parkinson’s disease and increases the neurotoxicity of DOPAL. Mol. Cell. Neurosci. 2017, 85, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Bartels, T.; Choi, J.G.; Selkoe, D.J. α-synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 2011, 477, 107–110. [Google Scholar] [CrossRef] [PubMed]
- Dettmer, U.; Newman, A.J.; Soldner, F.; Luth, E.S.; Kim, N.C.; von Saucken, V.E.; Sanderson, J.B.; Jaenisch, R.; Bartels, T.; Selkoe, D. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat. Commun. 2015, 6, 7314. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Salminen, L.E.; Paul, R.H. Oxidative stress and genetic markers of suboptimal antioxidant defense in the aging brain: A theoretical review. Rev. Neurosci. 2014, 25, 805–819. [Google Scholar] [CrossRef] [PubMed]
- Maruyama, W.; Shaomoto-Nagai, M.; Kato, Y.; Hisaka, S.; Osawa, T.; Naoi, M. Role of lipid peroxide in the neurodegenerative disorders. Subcell. Biochem. 2014, 77, 127–136. [Google Scholar] [PubMed]
- Ward, R.J.; Zucca, F.A.; Duyn, J.H.; Crichton, R.R.; Zecca, L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014, 13, 1045–1060. [Google Scholar] [CrossRef] [Green Version]
- Flowers, A.; Bell-Temin, H.; Jalloh, A.; Stevens, S.M., Jr.; Bickford, P.C. Proteomic analysis of aged microglia: Shifts in transcription, bioenergetics, and nutrient response. J. Neuroinflamm. 2017, 14, 96. [Google Scholar] [CrossRef] [PubMed]
- Orre, M.; Kamphuis, W.; Osborn, L.M.; Melief, J.; Kooijman, L.; Huitinga, I.; Klooster, J.; Bossers, K.; Hol, E.M. Acute isolation and transcriptome characterization of cortical astrocytes and microglia from young and aged mice. Neurobiol. Aging 2014, 35, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Holtman, I.R.; Raj, D.D.; Miller, J.A.; Schaafsma, W.; Yin, Z.; Brouwer, N.; Wes, P.D.; Moller, T.; Orre, M.; Kamphuis, W.; et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: A co-expression meta-analysis. Acta Neuropathol. Commun. 2015, 3, 31. [Google Scholar] [CrossRef] [PubMed]
- Wehrspaun, C.C.; Haerty, W.; Ponting, C.P. Microglia recapitulate a hematopoietic master regulator network in the aging human frontal cortex. Neurobiol. Aging 2015, 36, 2443.e9–2443.e20. [Google Scholar] [CrossRef] [PubMed]
- Sikora, E.; Arendt, T.; Bennett, M.; Narita, M. Impact of cellular senescence signature on ageing research. Ageing Res. Rev. 2011, 10, 146–152. [Google Scholar] [CrossRef] [PubMed]
- Giulian, D.; Baker, T.J. Characterization of ameboid microglia isolated from developing mammalian brain. J. Neurosci. Off. J. Soc. Neurosci. 1986, 6, 2163–2178. [Google Scholar] [CrossRef] [Green Version]
- Caldeira, C.; Oliveira, A.F.; Cunha, C.; Vaz, A.R.; Falcao, A.S.; Fernandes, A.; Brites, D. Microglia change from a reactive to an age-like phenotype with the time in culture. Front. Cell. Neurosci. 2014, 8, 152. [Google Scholar] [CrossRef] [PubMed]
- Ransohoff, R.M.; Perry, V.H. Microglial physiology: Unique stimuli, specialized responses. Annu. Rev. Immunol. 2009, 27, 119–145. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.K.; Tansey, M.G. Microglia isolation from adult mouse brain. Methods Mol. Biol. 2013, 1041, 17–23. [Google Scholar] [PubMed]
- Zeineh, M.M.; Chen, Y.; Kitzler, H.H.; Hammond, R.; Vogel, H.; Rutt, B.K. Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Neurobiol. Aging 2015, 36, 2483–2500. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Von Bernhardi, R.; Tichauer, J.E.; Eugenin, J. Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J. Neurochem. 2010, 112, 1099–1114. [Google Scholar] [CrossRef] [PubMed]
- Streit, W.J.; Sammons, N.W.; Kuhns, A.J.; Sparks, D.L. Dystrophic microglia in the aging human brain. Glia 2004, 45, 208–212. [Google Scholar] [CrossRef] [PubMed]
- Meng, F.X.; Hou, J.M.; Sun, T.S. In vivo evaluation of microglia activation by intracranial iron overload in central pain after spinal cord injury. J. Orthop. Surg. Res. 2017, 12, 75. [Google Scholar] [CrossRef] [PubMed]
- Healy, S.; McMahon, J.; Owens, P.; FitzGerald, U. Significant glial alterations in response to iron loading in a novel organotypic hippocampal slice culture model. Sci. Rep. 2016, 6, 36410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saleppico, S.; Mazzolla, R.; Boelaert, J.R.; Puliti, M.; Barluzzi, R.; Bistoni, F.; Blasi, E. Iron regulates microglial cell-mediated secretory and effector functions. Cell. Immunol. 1996, 170, 251–259. [Google Scholar] [CrossRef] [PubMed]
- Charolidi, N.; Schilling, T.; Eder, C. Microglial Kv1.3 channels and P2Y12 receptors differentially regulate cytokine and chemokine release from brain slices of young adult and aged mice. PLoS ONE 2015, 10, e0128463. [Google Scholar] [CrossRef] [PubMed]
- Cunningham, C. Microglia and neurodegeneration: The role of systemic inflammation. Glia 2013, 61, 71–90. [Google Scholar] [CrossRef] [PubMed]
- Sanchez-Guajardo, V.; Tentillier, N.; Romero-Ramos, M. The relation between α-synuclein and microglia in Parkinson’s disease: Recent developments. Neuroscience 2015, 302, 47–58. [Google Scholar] [CrossRef] [PubMed]
- Mandler, M.; Valera, E.; Rockenstein, E.; Mante, M.; Weninger, H.; Patrick, C.; Adame, A.; Schmidhuber, S.; Santic, R.; Schneeberger, A.; et al. Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol. Neurodegener. 2015, 10, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bachstetter, A.D.; Van Eldik, L.J.; Schmitt, F.A.; Neltner, J.H.; Ighodaro, E.T.; Webster, S.J.; Patel, E.; Abner, E.L.; Kryscio, R.J.; Nelson, P.T. Disease-related microglia heterogeneity in the hippocampus of Alzheimer’s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol. Commun. 2015, 3, 32. [Google Scholar] [CrossRef] [PubMed]
- Spittau, B. Aging microglia-phenotypes, functions and implications for age-related neurodegenerative diseases. Front. Aging Neurosci. 2017, 9, 194. [Google Scholar] [CrossRef] [PubMed]
- Sharaf, A.; Krieglstein, K.; Spittau, B. Distribution of microglia in the postnatal murine nigrostriatal system. Cell Tissue Res. 2013, 351, 373–382. [Google Scholar] [CrossRef] [PubMed]
- Shtilerman, M.D.; Ding, T.T.; Lansbury, P.T., Jr. Molecular crowding accelerates fibrillization of α-synuclein: Could an increase in the cytoplasmic protein concentration induce Parkinson’s disease? Biochemistry 2002, 41, 3855–3860. [Google Scholar] [CrossRef] [PubMed]
- Bai, J.; Liu, M.; Pielak, G.J.; Li, C. Macromolecular and small molecular crowding have similar effects on α-synuclein structure. ChemPhysChem 2017, 18, 55–58. [Google Scholar] [CrossRef] [PubMed]
- Hayden, M.S.; Ghosh, S. Regulation of NF-κB by TNF family cytokines. Semin. Immunol. 2014, 26, 253–266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- De Maturana, R.L.; Lang, V.; Zubiarrain, A.; Sousa, A.; Vazquez, N.; Gorostidi, A.; Aguila, J.; de Munain, A.L.; Rodriguez, M.; Sanchez-Pernaute, R. Mutations in LRRK2 impair NF-κB pathway in iPSC-derived neurons. J. Neuroinflamm. 2016, 13, 295. [Google Scholar] [CrossRef] [PubMed]
- Wang, M.X.; Cheng, X.Y.; Jin, M.; Cao, Y.L.; Yang, Y.P.; Wang, J.D.; Li, Q.; Wang, F.; Hu, L.F.; Liu, C.F. TNF compromises lysosome acidification and reduces α-synuclein degradation via autophagy in dopaminergic cells. Exp. Neurol. 2015, 271, 112–121. [Google Scholar] [CrossRef] [PubMed]
- Garcia-Esparcia, P.; Llorens, F.; Carmona, M.; Ferrer, I. Complex deregulation and expression of cytokines and mediators of the immune response in Parkinson’s disease brain is region dependent. Brain Pathol. 2014, 24, 584–598. [Google Scholar] [CrossRef] [PubMed]
- Hunot, S.; Brugg, B.; Ricard, D.; Michel, P.P.; Muriel, M.P.; Ruberg, M.; Faucheux, B.A.; Agid, Y.; Hirsch, E.C. Nuclear translocation of NF-κB is increased in dopaminergic neurons of patients with Parkinson disease. Proc. Natl. Acad. Sci. USA 1997, 94, 7531–7536. [Google Scholar] [CrossRef] [PubMed]
- Ghosh, A.; Roy, A.; Liu, X.; Kordower, J.H.; Mufson, E.J.; Hartley, D.M.; Ghosh, S.; Mosley, R.L.; Gendelman, H.E.; Pahan, K. Selective inhibition of NF-κB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease. Proc. Natl. Acad. Sci. USA 2007, 104, 18754–18759. [Google Scholar] [CrossRef] [PubMed]
- Pranski, E.; Van Sanford, C.D.; Dalal, N.; Orr, A.L.; Karmali, D.; Cooper, D.S.; Gearing, M.; Lah, J.J.; Levey, A.I.; Betarbet, R. NF-κB activity is inversely correlated to RNF11 expression in Parkinson’s disease. Neurosci. Lett. 2013, 547, 16–20. [Google Scholar] [CrossRef] [PubMed]
- Koziorowski, D.; Tomasiuk, R.; Szlufik, S.; Friedman, A. Inflammatory cytokines and NT-proCNP in Parkinson’s disease patients. Cytokine 2012, 60, 762–766. [Google Scholar] [CrossRef] [PubMed]
- Kim, C.; Ho, D.H.; Suk, J.E.; You, S.; Michael, S.; Kang, J.; Joong Lee, S.; Masliah, E.; Hwang, D.; Lee, H.J.; et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 2013, 4, 1562. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kim, C.; Lee, H.J.; Masliah, E.; Lee, S.J. Non-cell-autonomous neurotoxicity of α-synuclein through microglial Toll-like receptor 2. Exp. Neurobiol. 2016, 25, 113–119. [Google Scholar] [CrossRef] [PubMed]
- Tan, J.C.; Indelicato, S.R.; Narula, S.K.; Zavodny, P.J.; Chou, C.C. Characterization of Interleukin-10 receptors on human and mouse cells. J. Biol. Chem. 1993, 268, 21053–21059. [Google Scholar] [PubMed]
- Wang, W.; Perovic, I.; Chittuluru, J.; Kaganovich, A.; Nguyen, L.T.; Liao, J.; Auclair, J.R.; Johnson, D.; Landeru, A.; Simorellis, A.K.; et al. A soluble α-synuclein construct forms a dynamic tetramer. Proc. Natl. Acad. Sci. USA 2011, 108, 17797–17802. [Google Scholar] [CrossRef] [PubMed]
- Giraldez-Perez, R.; Antolin-Vallespin, M.; Munoz, M.; Sanchez-Capelo, A. Models of α-synuclein aggregation in Parkinson’s disease. Acta Neuropathol. Commun. 2014, 2, 176. [Google Scholar] [CrossRef] [PubMed]
- Roberts, H.L.; Brown, D.R. Seeking a mechanism for the toxicity of oligomeric α-synuclein. Biomolecules 2015, 5, 282–305. [Google Scholar] [CrossRef] [PubMed]
C8B4 Microglia | Primary Mouse Microglia | |||
---|---|---|---|---|
Cytokine (ng/mg) | Control | Iron-Fed | Control | Iron-Fed |
TNFα | 142.82 ± 12.40 | 192.46 ± 5.52 * | 37.42 ± 3.74 | 84.19 ± 3.45 * |
IFNγ | n.d. | n.d. | n.d. | n.d. |
KC/GRO | n.d. | n.d. | 698 ± 16 | 2113 ± 398 * |
IL-1b | 2.93 ± 0.27 | 3.83 ± 0.22 * | 0.99 ± 0.08 | 0.34 ± 0.03 * |
IL-2 | n.d. | n.d. | n.d. | n.d. |
IL-4 | n.d. | n.d. | n.d. | n.d. |
IL-5 | n.d. | n.d. | n.d. | n.d. |
IL-6 | 490.96 ± 49.77 | 430.77 ± 18.05 | 356.09 ±4 7.84 | 117.56 ± 24.22 * |
IL-8 | n.d. | n.d. | n.d. | n.d. |
IL-10 | 6.20 ± 1.04 | 0.84 ± 0.26 * | 5.00 ± 0.37 | 10.34 ± 0.98 * |
IL-12p70 | n.d. | n.d. | n.d. | n.d. |
IL-13 | n.d. | n.d. | n.d. | n.d. |
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Angelova, D.M.; Brown, D.R. Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity. Biomolecules 2018, 8, 67. https://doi.org/10.3390/biom8030067
Angelova DM, Brown DR. Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity. Biomolecules. 2018; 8(3):67. https://doi.org/10.3390/biom8030067
Chicago/Turabian StyleAngelova, Dafina M., and David R. Brown. 2018. "Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity" Biomolecules 8, no. 3: 67. https://doi.org/10.3390/biom8030067