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Cited by 66Advanced Glycation End Products researchAmyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatments

Receptor for Advanced Glycation End Products and its Inflammatory Ligands are Upregulated in Amyotrophic Lateral Sclerosis

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Juranek, Judyta K., Daffu, Gurdip K., Wojtkiewicz, Joanna, Lacomis, David, Kofler, Julia, Schmidt, Ann Marie·2015·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2015.00485PMC PMC4686801
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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder of largely unknown pathogenesis. Recent studies suggest that enhanced oxidative stress and neuroinflammation contribute to the progression of the disease. Mounting evidence implicates the receptor for advanced glycation end-products (RAGE) as a significant contributor to the pathogenesis of certain neurodegenerative diseases and chronic conditions. It is hypothesized that detrimental actions of RAGE are triggered upon binding to its ligands, such as AGEs (advanced glycation end products), S100/calgranulin family members, and High Mobility Group Box-1 (HMGB1) proteins. Here, we examined the expression of RAGE and its ligands in human ALS spinal cord. Tissue samples from age-matched human control and ALS spinal cords were tested for the expression of RAGE, carboxymethyllysine (CML) AGE, S100B, and HMGB1, and intensity of the immunofluorescent and immunoblotting signals was assessed. We found that the expression of both RAGE and its ligands was significantly increased in the spinal cords of ALS patients versus age-matched control subjects. Our study is the first report describing co-expression of both RAGE and its ligands in human ALS spinal cords. These findings suggest that further probing of RAGE as a mechanism of neurodegeneration in human ALS is rational.

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  • Levels of RAGE and its ligands (e.g., AGEs) were increased in the spinal cord and cerebrospinal fluid of ALS patients.

    “The levels of RAGE and its ligands (e.g., AGEs) were increased in the spinal cord and cerebrospinal fluid (CSF) of ALS patients.299,341”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [341]

    The Results section reports increased RAGE and its ligands, including the AGE CML, in ALS spinal cord compared with controls. The paper examines spinal cord tissue, not cerebrospinal fluid; it does not support the claimed increase in CSF. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

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  1. Andersson A. Covacu R. Sunnemark D. Danilov A. I. Dal Bianco A. Khademi M. (2008). Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. J. Leukoc. Biol. 84 1248– 1255. 10.1189/jlb.1207844 18644848 · DOI
  2. Anzilotti S. Giampa C. Laurenti D. Perrone L. Bernardi G. Melone M. A. (2012). Immunohistochemical localization of receptor for advanced glycation end (RAGE) products in the R6/2 mouse model of Huntington’s disease. Brain Res. Bull. 87 350– 358. 10.1016/j.brainresbull.2011.01.009 21272617 · DOI
  3. Bianchi R. Adami C. Giambanco I. Donato R. (2007). S100B binding to RAGE in microglia stimulates COX-2 expression. J. Leukoc. Biol. 81 108– 118. 10.1189/jlb.0306198 17023559 · DOI
  4. 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 31 665– 677. 10.1016/j.neurobiolaging.2008.05.017 18599158 · DOI
  5. 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 7214– 7226. 10.1074/jbc.M110.169342 21209080 PMC3044978 · DOI
  6. Bierhaus A. Haslbeck K. M. Humpert P. M. Liliensiek B. Dehmer T. Morcos M. (2004). Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J. Clin. Invest. 114 1741– 1751. 10.1172/JCI18058 15599399 PMC535062 · DOI
  7. Brites D. Vaz A. R. (2014). Microglia centered pathogenesis in ALS: insights in cell interconnectivity. Front Cell Neurosci 8: 117 10.3389/fncel.2014.00117 PMC4033073 24904276 · DOI
  8. Cho H. J. Son S. M. Jin S. M. Hong H. S. Shin D. H. Kim S. J. (2009). RAGE regulates BACE1 and Abeta generation via NFAT1 activation in Alzheimer’s disease animal model. FASEB J. 23 2639– 2649. 10.1096/fj.08-126383 19332646 · DOI
  9. Daborg J. Von Otter M. Sjolander A. Nilsson S. Minthon L. Gustafson D. R. (2010). Association of the RAGE G82S polymorphism with Alzheimer’s disease. J. Neural. Transm. 117 861– 867. 10.1007/s00702-010-0437-0 20567859 PMC2895876 · DOI
  10. Ding Q. Keller J. N. (2005). Evaluation of rage isoforms, ligands, and signaling in the brain. Biochim. Biophys. Acta 1746 18– 27. 10.1016/j.bbamcr.2005.08.006 16214242 · DOI
  11. Donato R. (2001). S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int. J. Biochem. Cell Biol. 33 637– 668. 10.1016/S1357-2725(01)00046-2 11390274 · DOI · Paper page
  12. Edwards M. M. Robinson S. R. (2006). TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer’s disease. J. Neural. Transm. 113 1709– 1715. 10.1007/s00702-006-0479-5 16736247 · DOI
  13. Emanuele E. D’angelo A. Tomaino C. Binetti G. Ghidoni R. Politi P. (2005). Circulating levels of soluble receptor for advanced glycation end products in Alzheimer disease and vascular dementia. Arch. Neurol. 62 1734– 1736. 10.1001/archneur.62.11.1734 16286548 · DOI
  14. Frakes A. E. Ferraiuolo L. Haidet-Phillips A. M. Schmelzer L. Braun L. Miranda C. J. (2014). Microglia induce motor neuron death via the classical NF-kappaB pathway in amyotrophic lateral sclerosis. Neuron 81 1009– 1023. 10.1016/j.neuron.2014.01.013 24607225 PMC3978641 · DOI · Paper page
  15. Gao H. M. Zhou H. Zhang F. Wilson B. C. Kam W. Hong J. S. (2011). HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. J. Neurosci. 31 1081– 1092. 10.1523/JNEUROSCI.3732-10.2011 21248133 PMC3046932 · DOI · Paper page
  16. Grillo M. A. Colombatto S. (2008). Advanced glycation end-products (AGEs): involvement in aging and in neurodegenerative diseases. Amino Acids 35 29– 36. 10.1007/s00726-007-0606-0 18008028 · DOI
  17. Hall E. D. Oostveen J. A. Gurney M. E. (1998). Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23 249– 256. 10.1002/(SICI)1098-1136(199807)23:3<249::AID-GLIA7>3.0.CO;2-# 9633809 · DOI
  18. Hearst S. M. Walker L. R. Shao Q. Lopez M. Raucher D. Vig P. J. (2011). The design and delivery of a thermally responsive peptide to inhibit S100B-mediated neurodegeneration. Neuroscience 197 369– 380. 10.1016/j.neuroscience.2011.09.025 21958864 PMC3210406 · DOI
  19. Henkel J. S. Engelhardt J. I. Siklos L. Simpson E. P. Kim S. H. Pan T. (2004). Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann. Neurol. 55 221– 235. 10.1002/ana.10805 14755726 · DOI
  20. Hofmann M. A. Drury S. Fu C. Qu W. Taguchi A. Lu Y. (1999). RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97 889– 901. 10.1016/S0092-8674(00)80801-6 10399917 · DOI · Paper page
  21. Huttunen H. J. Kuja-Panula J. Sorci G. Agneletti A. L. Donato R. Rauvala H. (2000). Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J. Biol. Chem. 275 40096– 40105. 10.1074/jbc.M006993200 11007787 · DOI
  22. Ilzecka J. (2009). Serum-soluble receptor for advanced glycation end product levels in patients with amyotrophic lateral sclerosis. Acta Neurol. Scand. 120 119– 122. 10.1111/j.1600-0404.2008.01133.x 19053950 · DOI
  23. Juranek J. Ray R. Banach M. Rai V. (2015). Receptor for advanced glycation end-products in neurodegenerative diseases. Rev. Neurosci. 26 691– 698. 10.1515/revneuro-2015-0003 26226128 · DOI
  24. Juranek J. K. Geddis M. S. Rosario R. Schmidt A. M. (2013a). Impaired slow axonal transport in diabetic peripheral nerve is independent of RAGE. Eur. J. Neurosci. 38 3159– 3168. 10.1111/ejn.12333 23941591 · DOI
  25. Juranek J. K. Kothary P. Mehra A. Hays A. Brannagan T. H. III Schmidt A. M. (2013b). Increased expression of the receptor for advanced glycation end-products in human peripheral neuropathies. Brain Behav. 3 701– 709. 10.1002/brb3.176 24363972 PMC3868174 · DOI
  26. Kikuchi S. Shinpo K. Ogata A. Tsuji S. Takeuchi M. Makita Z. (2002). Detection of N epsilon-(carboxymethyl) lysine (CML) and non-CML advanced glycation end-products in the anterior horn of amyotrophic lateral sclerosis spinal cord. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 3 63– 68. 10.1080/146608202760196020 12215227 · DOI
  27. Li K. Dai D. Zhao B. Yao L. Yao S. Wang B. (2010). Association between the RAGE G82S polymorphism and Alzheimer’s disease. J. Neural. Transm. 117 97– 104. 10.1007/s00702-009-0334-6 19902324 · DOI
  28. Liang F. Jia J. Wang S. Qin W. Liu G. (2013). Decreased plasma levels of soluble low density lipoprotein receptor-related protein-1 (sLRP) and the soluble form of the receptor for advanced glycation end products (sRAGE) in the clinical diagnosis of Alzheimer’s disease. J. Clin. Neurosci. 20 357– 361. 10.1016/j.jocn.2012.06.005 23228658 · DOI
  29. Lo Coco D. Veglianese P. Allievi E. Bendotti C. (2007). Distribution and cellular localization of high mobility group box protein 1 (HMGB1) in the spinal cord of a transgenic mouse model of ALS. Neurosci. Lett. 412 73– 77. 10.1016/j.neulet.2006.10.063 17196331 · DOI
  30. Lue L. F. Walker D. G. Brachova L. Beach T. G. Rogers J. Schmidt A. M. (2001). Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism. Exp. Neurol. 171 29– 45. 10.1006/exnr.2001.7732 11520119 · DOI · Paper page
  31. Ma L. Nicholson L. F. (2004). Expression of the receptor for advanced glycation end products in Huntington’s disease caudate nucleus. Brain Res. 1018 10– 17. 10.1016/j.brainres.2004.05.052 15262199 · DOI
  32. Mattson M. P. (2004). Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative disorders. Ann. N. Y. Acad. Sci. 1012 37– 50. 10.1196/annals.1306.004 15105254 · DOI
  33. Mattson M. P. Camandola S. (2001). NF-kappaB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest. 107 247– 254. 10.1172/JCI11916 11160145 PMC199201 · DOI · Paper page
  34. Mazarati A. Maroso M. Iori V. Vezzani A. Carli M. (2011). High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and Receptor for Advanced Glycation End Products. Exp. Neurol. 232 143– 148. 10.1016/j.expneurol.2011.08.012 21884699 PMC3202022 · DOI
  35. Mitchell J. D. Borasio G. D. (2007). Amyotrophic lateral sclerosis. Lancet 369 2031– 2041. 10.1016/S0140-6736(07)60944-1 17574095 · DOI
  36. Prasad K. Prabhu G. K. (2012). Image analysis tools for evaluation of microscopic views of immunohistochemically stained specimen in medical research-a review. J. Med. Syst. 36 2621– 2631. 10.1007/s10916-011-9737-7 21584771 · DOI
  37. Rojas F. Gonzalez D. Cortes N. Ampuero E. Hernandez D. E. Fritz E. (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 10.3389/fncel.2015.00203 PMC4460879 26106294 · DOI
  38. Rowland L. P. Shneider N. A. (2001). Amyotrophic lateral sclerosis. N. Engl. J. Med. 344 1688– 1700. 10.1056/NEJM200105313442207 11386269 · DOI
  39. Saleh A. Smith D. R. Tessler L. Mateo A. R. Martens C. Schartner E. (2013). Receptor for advanced glycation end-products (RAGE) activates divergent signaling pathways to augment neurite outgrowth of adult sensory neurons. Exp. Neurol. 249 149– 159. 10.1016/j.expneurol.2013.08.018 24029001 · DOI
  40. Sathe K. Maetzler W. Lang J. D. Mounsey R. B. Fleckenstein C. Martin H. L. (2012). S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain 135 3336– 3347. 10.1093/brain/aws250 23169921 PMC3501971 · DOI · Paper page
  41. Schmidt A. M. (2015). Soluble RAGEs - Prospects for treating & tracking metabolic and inflammatory disease. Vascul Pharmacol. 72 1– 8. 10.1016/j.vph.2015.06.011 26130225 PMC4547874 · DOI
  42. Schmidt A. M. Yan S. D. Yan S. F. Stern D. M. (2000). The biology of the receptor for advanced glycation end products and its ligands. Biochim. Biophys. Acta 1498 99– 111. 10.1016/S0167-4889(00)00087-2 11108954 · DOI
  43. Schmitt A. Bertsch T. Henning U. Tost H. Klimke A. Henn F. A. (2005). Increased serum S100B in elderly, chronic schizophrenic patients: negative correlation with deficit symptoms. Schizophr. Res. 80 305– 313. 10.1016/j.schres.2005.04.013 15964742 · DOI
  44. Shibata N. Hirano A. Kato S. Nagai R. Horiuchi S. Komori T. (1999). Advanced glycation endproducts are deposited in neuronal hyaline inclusions: a study on familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. Acta Neuropathol. 97 240– 246. 10.1007/s004010050980 10090670 · DOI
  45. Shibata N. Nagai R. Miyata S. Jono T. Horiuchi S. Hirano A. (2000). Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. Acta Neuropathol. 100 275– 284. 10.1007/s004019900173 10965797 · DOI
  46. Shobha K. Alladi P. A. Nalini A. Sathyaprabha T. N. Raju T. R. (2010). Exposure to CSF from sporadic amyotrophic lateral sclerosis patients induces morphological transformation of astroglia and enhances GFAP and S100beta expression. Neurosci. Lett. 473 56– 61. 10.1016/j.neulet.2010.02.022 20170712 · DOI
  47. Sussmuth S. D. Sperfeld A. D. Hinz A. Brettschneider J. Endruhn S. Ludolph A. C. (2010). CSF glial markers correlate with survival in amyotrophic lateral sclerosis. Neurology 74 982– 987. 10.1212/WNL.0b013e3181d5dc3b 20308682 · DOI
  48. Takata K. Kitamura Y. Tsuchiya D. Kawasaki T. Taniguchi T. Shimohama S. (2004). High mobility group box protein-1 inhibits microglial Abeta clearance and enhances Abeta neurotoxicity. J. Neurosci. Res. 78 880– 891. 10.1002/jnr.20340 15499593 · DOI
  49. Takata K. Takada T. Ito A. Asai M. Tawa M. Saito Y. (2012). Microglial amyloid-beta1-40 phagocytosis dysfunction is caused by high-mobility group box protein-1: implications for the pathological progression of Alzheimer’s disease. Int. J. Alzheimers Dis. 2012: 685739 10.1155/2012/685739 PMC3357001 22645697 · DOI
  50. Tang D. Kang R. Zeh H. J. III Lotze M. T. (2011). High-mobility group box 1, oxidative stress, and disease. Antioxid. Redox. Signal. 14 1315– 1335. 10.1089/ars.2010.3356 20969478 PMC3048826 · DOI
  51. Teismann P. Sathe K. Bierhaus A. Leng L. Martin H. L. Bucala R. (2012). Receptor for advanced glycation endproducts (RAGE) deficiency protects against MPTP toxicity. Neurobiol. Aging 33 2478– 2490. 10.1016/j.neurobiolaging.2011.12.006 22227007 PMC3712169 · DOI · Paper page
  52. Valente T. Gella A. Fernandez-Busquets X. Unzeta M. Durany N. (2010). Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol. Dis. 37 67– 76. 10.1016/j.nbd.2009.09.008 19778613 · DOI
  53. Vogel C. Marcotte E. M. (2012). Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. 13 227– 232. 10.1038/nrg3185 22411467 PMC3654667 · DOI · Paper page
  54. Wang M. Y. Ross-Cisneros F. N. Aggarwal D. Liang C. Y. Sadun A. A. (2009). Receptor for advanced glycation end products is upregulated in optic neuropathy of Alzheimer’s disease. Acta Neuropathol. 118 381– 389. 10.1007/s00401-009-0513-4 19277685 PMC2867613 · DOI · Paper page
  55. Yan S. F. Yan S. D. Ramasamy R. Schmidt A. M. (2009). Tempering the wrath of RAGE: an emerging therapeutic strategy against diabetic complications, neurodegeneration, and inflammation. Ann. Med. 41 408– 422. 10.1080/07853890902806576 19322705 PMC2932796 · DOI

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Authors
Juranek, J. K., Daffu, G. K., Wojtkiewicz, J., Lacomis, D., Kofler, J., & Schmidt, A. M.
Affiliations
  • Columbia University Irving Medical Center (US)
  • NYU Langone Health (US)
  • University of Warmia and Mazury in Olsztyn (PL)
  • University of Pittsburgh (US)
Corresponding author
  • Juranek, Judyta K.
  • Schmidt, Ann Marie
ORCID
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2015-12-22
Volume
9
Pages
485-485
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2015.00485
PMC
PMC4686801
OpenAlex
W2239259805
Cited by
66
References
6
Citations by year
2026: 2 · 2025: 8 · 2024: 1 · 2023: 4 · 2022: 9 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 6 · 2017: 10 · 2016: 8
FWCI
6.57
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
amyotrophic lateral sclerosis, receptor for advanced glycation end products, advanced glycation end products, carboxymethyllysine, S100B, high mobility group box 1, neuroinflammation, oxidative stress, spinal cord, neurodegeneration, RAGE ligands

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