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Absence of Receptor for Advanced Glycation End Product (RAGE) Reduces Inflammation and Extends Survival in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron degenerative disease that is without effective treatment. The receptor for advanced glycation end products (RAGE) is a major component of the innate immune system that has been implicated in ALS pathogenesis. However, the contribution of RAGE signalling to the neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study therefore generated SOD1G93A mice lacking RAGE and compared them with SOD1G93A transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior muscle. We found that complete absence of RAGE signalling exerted a protective effect on SOD1G93A pathology, slowing disease progression and significantly extending survival by ~ 3 weeks and improving motor function (rotarod and grip strength). This was associated with reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis anterior muscle. We also documented that RAGE mRNA expression was significantly increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, supporting a widespread involvement for RAGE in ALS pathology. In summary, our results indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration in ALS and highlights RAGE as a potential immune therapeutic target for ALS.

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References

  1. Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z et al (2017) Amyotrophic lateral sclerosis. Nat Rev Dis Primers 3:17085. https://doi.org/10.1038/nrdp.2017.85

    Article  PubMed  Google Scholar 

  2. Lee JD, Coulthard LG, Woodruff TM (2019) Complement dysregulation in the central nervous system during development and disease. Semin Immunol 45:101340. https://doi.org/10.1016/j.smim.2019.101340

    Article  CAS  PubMed  Google Scholar 

  3. McCombe PA, Lee JD, Woodruff TM, Henderson RD (2020) The peripheral immune system and amyotrophic lateral sclerosis. Front Neurol 11:279. https://doi.org/10.3389/fneur.2020.00279

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ray R, Juranek JK, Rai V (2016) RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis. Neurosci Biobehav Rev 62:48–55. https://doi.org/10.1016/j.neubiorev.2015.12.006

    Article  CAS  PubMed  Google Scholar 

  5. Brites D, Vaz AR (2014) Microglia centered pathogenesis in ALS: insights in cell interconnectivity. Front Cell Neurosci 8:117. https://doi.org/10.3389/fncel.2014.00117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Casula M, Iyer AM, Spliet WG, Anink JJ, Steentjes K, Sta M, Troost D, Aronica E (2011) Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue. Neuroscience 179:233–243. https://doi.org/10.1016/j.neuroscience.2011.02.001

    Article  CAS  PubMed  Google Scholar 

  7. Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145. https://doi.org/10.1146/annurev.immunol.021908.132528

    Article  CAS  PubMed  Google Scholar 

  8. Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL (2001) Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 280(5):E685–E694. https://doi.org/10.1152/ajpendo.2001.280.5.E685

    Article  CAS  PubMed  Google Scholar 

  9. Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK et al (2014) Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron 81(5):1009–1023. https://doi.org/10.1016/j.neuron.2014.01.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Juranek JK, Daffu GK, Geddis MS, Li H, Rosario R, Kaplan BJ, Kelly L, Schmidt AM (2016) Soluble RAGE treatment delays progression of amyotrophic lateral sclerosis in SOD1 mice. Front Cell Neurosci 10:117. https://doi.org/10.3389/fncel.2016.00117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Juranek JK, Daffu GK, Wojtkiewicz J, Lacomis D, Kofler J, Schmidt AM (2015) Receptor for advanced glycation end products and its inflammatory ligands are upregulated in amyotrophic lateral sclerosis. Front Cell Neurosci 9:485. https://doi.org/10.3389/fncel.2015.00485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Serrano A, Donno C, Giannetti S, Peric M, Andjus P, D’Ambrosi N, Michetti F (2017) The astrocytic S100B protein with its receptor RAGE is aberrantly expressed in SOD1(G93A) models, and its inhibition decreases the expression of proinflammatory genes. Mediat Inflamm 2017:1626204–1626214. https://doi.org/10.1155/2017/1626204

    Article  CAS  Google Scholar 

  13. Kim MJ, Vargas MR, Harlan BA, Killoy KM, Ball LE, Comte-Walters S, Gooz M, Yamamoto Y et al (2018) Nitration and glycation turn mature NGF into a toxic factor for motor neurons: a role for p75(NTR) and RAGE signaling in ALS. Antioxid Redox Signal 28(18):1587–1602. https://doi.org/10.1089/ars.2016.6966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee JD, Kamaruzaman NA, Fung JN, Taylor SM, Turner BJ, Atkin JD, Woodruff TM, Noakes PG (2013) Dysregulation of the complement cascade in the hSOD1G93A transgenic mouse model of amyotrophic lateral sclerosis. J Neuroinflammation 10:119. https://doi.org/10.1186/1742-2094-10-119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arnold ES, Ling SC, Huelga SC, Lagier-Tourenne C, Polymenidou M, Ditsworth D, Kordasiewicz HB, McAlonis-Downes M et al (2013) ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A 110(8):E736–E745. https://doi.org/10.1073/pnas.1222809110

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chand KK, Lee KM, Lee JD, Qiu H, Willis EF, Lavidis NA, Hilliard MA, Noakes PG (2018) Defects in synaptic transmission at the neuromuscular junction precede motor deficits in a TDP-43(Q331K) transgenic mouse model of amyotrophic lateral sclerosis. FASEB J 32(5):2676–2689. https://doi.org/10.1096/fj.201700835R

    Article  PubMed  Google Scholar 

  17. Lee JD, Levin SC, Willis EF, Li R, Woodruff TM, Noakes PG (2018) Complement components are upregulated and correlate with disease progression in the TDP-43(Q331K) mouse model of amyotrophic lateral sclerosis. J Neuroinflammation 15(1):171. https://doi.org/10.1186/s12974-018-1217-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mitchell JC, Constable R, So E, Vance C, Scotter E, Glover L, Hortobagyi T, Arnold ES et al (2015) Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS. Acta Neuropathol Commun 3:36. https://doi.org/10.1186/s40478-015-0212-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wu MC, Gilmour TD, Mantovani S, Woodruff TM (2015) The receptor for advanced glycation endproducts does not contribute to pathology in a mouse mesenteric ischemia/reperfusion-induced injury model. Front Immunol 6:614. https://doi.org/10.3389/fimmu.2015.00614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Alexander GM, Erwin KL, Byers N, Deitch JS, Augelli BJ, Blankenhorn EP, Heiman-Patterson TD (2004) Effect of transgene copy number on survival in the G93A SOD1 transgenic mouse model of ALS. Brain Res Mol Brain Res 130(1–2):7–15. https://doi.org/10.1016/j.molbrainres.2004.07.002

    Article  CAS  PubMed  Google Scholar 

  21. Lee JY, Lee JD, Phipps S, Noakes PG, Woodruff TM (2015) Absence of toll-like receptor 4 (TLR4) extends survival in the hSOD1 G93A mouse model of amyotrophic lateral sclerosis. J Neuroinflammation 12:90. https://doi.org/10.1186/s12974-015-0310-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee JD, Liu N, Levin SC, Ottosson L, Andersson U, Harris HE, Woodruff TM (2019) Therapeutic blockade of HMGB1 reduces early motor deficits, but not survival in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. J Neuroinflammation 16(1):45. https://doi.org/10.1186/s12974-019-1435-2

    Article  PubMed  PubMed Central  Google Scholar 

  23. Watson C, Paxinos G, Kayalioglu G (2009) The spinal cord, First edn. Academic Press, London

    Google Scholar 

  24. Arbour D, Vande Velde C, Robitaille R (2017) New perspectives on amyotrophic lateral sclerosis: the role of glial cells at the neuromuscular junction. J Physiol 595(3):647–661. https://doi.org/10.1113/JP270213

    Article  CAS  PubMed  Google Scholar 

  25. Geloso MC, Corvino V, Marchese E, Serrano A, Michetti F, D’Ambrosi N (2017) The dual role of microglia in ALS: mechanisms and therapeutic approaches. Front Aging Neurosci 9:242. https://doi.org/10.3389/fnagi.2017.00242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487. https://doi.org/10.1038/nature21029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Philips T, Rothstein JD (2014) Glial cells in amyotrophic lateral sclerosis. Exp Neurol 262(Pt B):111–120. https://doi.org/10.1016/j.expneurol.2014.05.015

    Article  CAS  PubMed  Google Scholar 

  28. Bianchi R, Adami C, Giambanco I, Donato R (2007) S100B binding to RAGE in microglia stimulates COX-2 expression. J Leukoc Biol 81(1):108–118. https://doi.org/10.1189/jlb.0306198

    Article  CAS  PubMed  Google Scholar 

  29. Bianchi R, Giambanco I, Donato R (2010) S100B/RAGE-dependent activation of microglia via NF-kappaB and AP-1 co-regulation of COX-2 expression by S100B, IL-1beta and TNF-alpha. Neurobiol Aging 31(4):665–677. https://doi.org/10.1016/j.neurobiolaging.2008.05.017

    Article  CAS  PubMed  Google Scholar 

  30. Bianchi R, Kastrisianaki E, Giambanco I, Donato R (2011) S100B protein stimulates microglia migration via RAGE-dependent up-regulation of chemokine expression and release. J Biol Chem 286(9):7214–7226. https://doi.org/10.1074/jbc.M110.169342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fang F, Lue LF, Yan S, Xu H, Luddy JS, Chen D, Walker DG, Stern DM et al (2010) RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease. FASEB J 24(4):1043–1055. https://doi.org/10.1096/fj.09-139634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Phani S, Re DB, Przedborski S (2012) The role of the innate immune system in ALS. Front Pharmacol 3:150. https://doi.org/10.3389/fphar.2012.00150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, Liu S, Hegde A et al (2004) RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. EMBO J 23(20):4096–4105. https://doi.org/10.1038/sj.emboj.7600415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF, Yan SD (2007) RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer’s disease. Curr Mol Med 7(8):735–742. https://doi.org/10.2174/156652407783220741

    Article  CAS  PubMed  Google Scholar 

  35. Teismann P, Sathe K, Bierhaus A, Leng L, Martin HL, Bucala R, Weigle B, Nawroth PP et al (2012) Receptor for advanced glycation endproducts (RAGE) deficiency protects against MPTP toxicity. Neurobiol Aging 33(10):2478–2490. https://doi.org/10.1016/j.neurobiolaging.2011.12.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang Z, Li DD, Liang YY, Wang DS, Cai NS (2002) Activation of astrocytes by advanced glycation end products: cytokines induction and nitric oxide release. Acta Pharmacol Sin 23(11):974–980

    CAS  PubMed  Google Scholar 

  37. Apolloni S, Amadio S, Montilli C, Volonte C, D’Ambrosi N (2013) Ablation of P2X7 receptor exacerbates gliosis and motoneuron death in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. Hum Mol Genet 22(20):4102–4116. https://doi.org/10.1093/hmg/ddt259

    Article  CAS  PubMed  Google Scholar 

  38. Apolloni S, Amadio S, Parisi C, Matteucci A, Potenza RL, Armida M, Popoli P, D’Ambrosi N et al (2014) Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis. Dis Model Mech 7(9):1101–1109. https://doi.org/10.1242/dmm.017038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Meissner F, Molawi K, Zychlinsky A (2010) Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis. Proc Natl Acad Sci U S A 107(29):13046–13050. https://doi.org/10.1073/pnas.1002396107

    Article  PubMed  PubMed Central  Google Scholar 

  40. Rojas F, Gonzalez D, Cortes N, Ampuero E, Hernandez DE, Fritz E, Abarzua S, Martinez A et al (2015) Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of ALS through activation of c-Abl signaling. Front Cell Neurosci 9:203. https://doi.org/10.3389/fncel.2015.00203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wu DC, Re DB, Nagai M, Ischiropoulos H, Przedborski S (2006) The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc Natl Acad Sci U S A 103(32):12132–12137. https://doi.org/10.1073/pnas.0603670103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. De Paola M, Mariani A, Bigini P, Peviani M, Ferrara G, Molteni M, Gemma S, Veglianese P et al (2012) Neuroprotective effects of toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration. Mol Med 18:971–981. https://doi.org/10.2119/molmed.2012.00020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Deora V, Lee JD, Albornoz EA, McAlary L, Jagaraj CJ, Robertson AAB, Atkin JD, Cooper MA et al (2020) The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins. Glia 68(2):407–421. https://doi.org/10.1002/glia.23728

    Article  PubMed  Google Scholar 

  44. Johann S, Heitzer M, Kanagaratnam M, Goswami A, Rizo T, Weis J, Troost D, Beyer C (2015) NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia 63(12):2260–2273. https://doi.org/10.1002/glia.22891

    Article  PubMed  Google Scholar 

  45. Lee JD, Kumar V, Fung JN, Ruitenberg MJ, Noakes PG, Woodruff TM (2017) Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1(G93A) mouse model of amyotrophic lateral sclerosis. Br J Pharmacol 174(8):689–699. https://doi.org/10.1111/bph.13730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Woodruff TM, Lee JD, Noakes PG (2014) Role for terminal complement activation in amyotrophic lateral sclerosis disease progression. Proc Natl Acad Sci U S A 111(1):E3–E4. https://doi.org/10.1073/pnas.1321248111

    Article  CAS  PubMed  Google Scholar 

  47. Ma W, Rai V, Hudson BI, Song F, Schmidt AM, Barile GR (2012) RAGE binds C1q and enhances C1q-mediated phagocytosis. Cell Immunol 274(1–2):72–82. https://doi.org/10.1016/j.cellimm.2012.02.001

    Article  CAS  PubMed  Google Scholar 

  48. Zhao Y, Luo C, Chen J, Sun Y, Pu D, Lv A, Zhu S, Wu J et al (2018) High glucose-induced complement component 3 up-regulation via RAGE-p38MAPK-NF-kappaB signalling in astrocytes: in vivo and in vitro studies. J Cell Mol Med 22(12):6087–6098. https://doi.org/10.1111/jcmm.13884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sagheddu R, Chiappalupi S, Salvadori L, Riuzzi F, Donato R, Sorci G (2018) Targeting RAGE as a potential therapeutic approach to Duchenne muscular dystrophy. Hum Mol Genet 27(21):3734–3746. https://doi.org/10.1093/hmg/ddy288

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to sincerely thank Kym French for animal care and husbandry. We also thank Maryam Shayegh for her technical support with genotyping the mice and A/Prof Simon Phipps for the original supply of RAGE−/− breeders used to establish our colony.

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Funding

JDL was supported by the Motor Neuron Disease Research Institute of Australia (MNDRIA) Postdoctoral Fellowship (PDF1604) and the research was funded by a grant from the National Health and Medical Research Council (NHMRC; Project grant APP1082271).

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Authors and Affiliations

  1. School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia

    John D. Lee, Tanya S. McDonald, Jenny N. T. Fung & Trent M. Woodruff

  2. Queensland Brain Institute, the University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia

    Trent M. Woodruff

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Contributions

JDL and TMW conceived the project. JDL and TMW designed the study. JDL performed the experiments with assistance from TSM and JNTF. All authors contributed to the analyses and interpretation of the data. JDL wrote the paper with a contribution from TMW. All authors read and approved the final manuscript.

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Correspondence to Trent M. Woodruff.

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All experimental procedures were approved by the University of Queensland Animal Ethics Committee and complied with the policies and regulations regarding animal experimentation and other ethical matters. They were conducted in accordance with the Queensland Government Animal Research Act 2001, associated Animal Care and Protection Regulations (2002 and 2008), and the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, 8th Edition (National Health and Medical Research Council, 2013).

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Lee, J.D., McDonald, T.S., Fung, J.N.T. et al. Absence of Receptor for Advanced Glycation End Product (RAGE) Reduces Inflammation and Extends Survival in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis. Mol Neurobiol 57, 4143–4155 (2020). https://doi.org/10.1007/s12035-020-02019-9

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