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Role of RAGE in the Pathogenesis of Neurological Disorders

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Abstract

This review reflects upon our own as well as other investigators’ studies on the role of receptor for advanced glycation end-products (RAGE), bringing up the latest information on RAGE in physiology and pathology of the nervous system. Over the last ten years, major progress has been made in uncovering many of RAGE-ligand interactions and signaling pathways in nervous tissue; however, the translation of these discoveries into clinical practice has not come to fruition yet. This is likely, in part to be the result of our incomplete understanding of this crucial signaling pathway. Clinical trials examining the therapeutic efficacy of blocking RAGE-external ligand interactions by genetically engineered soluble RAGE or an endogenous RAGE antagonist, has not stood up to its promise; however, other trials with different blocking agents are being considered with hope for therapeutic success in diseases of the nervous system.

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References

  1. Teissier T, Boulanger É. The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging. Biogerontology 2019, 20: 279–301.

    Article  PubMed  CAS  Google Scholar 

  2. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 1992, 267: 14998–15004.

    Article  PubMed  CAS  Google Scholar 

  3. Brett J, Schmidt AM, Yan SD, Zou YS, Weidman E, Pinsky D, et al. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol 1993, 143: 1699–1712.

    PubMed  PubMed Central  CAS  Google Scholar 

  4. Schmidt AM, Hori O, Chen JX, Li JF, Crandall J, Zhang J, et al. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest 1995, 96: 1395–1403.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Peiretti PG, Medana C, Visentin S, Giancotti V, Zunino V, Meineri G. Determination of carnosine, anserine, homocarnosine, pentosidine and thiobarbituric acid reactive substances contents in meat from different animal species. Food Chem 2011, 126: 1939–1947.

    Article  PubMed  CAS  Google Scholar 

  6. Liu LC, Liu L, Xie JH, Shen MY. Formation mechanism of AGEs in Maillard reaction model systems containing ascorbic acid. Food Chem 2022, 378: 132108.

    Article  PubMed  CAS  Google Scholar 

  7. Koschinsky T, He CJ, Mitsuhashi T, Bucala R, Liu C, Buenting C, et al. Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci U S A 1997, 94: 6474–6479.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Scheijen JLJM, Clevers E, Engelen L, Dagnelie PC, Brouns F, Stehouwer CDA, et al. Analysis of advanced glycation endproducts in selected food items by ultra-performance liquid chromatography tandem mass spectrometry: presentation of a dietary AGE database. Food Chem 2016, 190: 1145–1150.

    Article  PubMed  CAS  Google Scholar 

  9. Sousa MM, Saraiva MJ. Neurodegeneration in familial amyloid polyneuropathy: from pathology to molecular signaling. Prog Neurobiol 2003, 71: 385–400.

    Article  PubMed  CAS  Google Scholar 

  10. Schmidt AM, Hori O, Cao R, Yan SD, Brett J, Wautier JL, et al. RAGE: a novel cellular receptor for advanced glycation end products. Diabetes 1996, 45: S77–S80.

    Article  PubMed  CAS  Google Scholar 

  11. Guo ZJ, Niu HX, Hou FF, Zhang L, Fu N, Nagai R, et al. Advanced oxidation protein products activate vascular endothelial cells via a RAGE-mediated signaling pathway. Antioxid Redox Signal 2008, 10: 1699–1712.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 1999, 97: 889–901.

    Article  PubMed  CAS  Google Scholar 

  13. Nogueira-Machado JA, de Oliveira Volpe CM. HMGB-1 as a target for inflammation controlling. Recent Pat Endocr Metab Immune Drug Discov 2012, 6: 201–209.

    Article  PubMed  CAS  Google Scholar 

  14. Rai V, Maldonado AY, Burz DS, Reverdatto S, Yan SF, Schmidt AM, et al. Signal transduction in receptor for advanced glycation end products (RAGE): solution structure of C-terminal rage (ctRAGE) and its binding to mDia1. J Biol Chem 2012, 287: 5133–5144.

    Article  PubMed  CAS  Google Scholar 

  15. Aboushousha T, Hammam O, Safwat G, Eesa A, Ahmed S, Esmat ME, et al. Differential expression of RAGE, EGFR and ki-67 in primary tumors and lymph node deposits of breast carcinoma. Asian Pac J Cancer Prev 2018, 19: 2269–2277.

    PubMed  PubMed Central  CAS  Google Scholar 

  16. Sakaguchi M, Murata H, Aoyama Y, Hibino T, Putranto EW, Ruma IMW, et al. DNAX-activating protein 10 (DAP10) membrane adaptor associates with receptor for advanced glycation end products (RAGE) and modulates the RAGE-triggered signaling pathway in human keratinocytes. J Biol Chem 2014, 289: 23389–23402.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Rao JL, Ye ZC, Tang H, Wang C, Peng H, Lai WY, et al. The RhoA/ROCK pathway ameliorates adhesion and inflammatory infiltration induced by AGEs in glomerular endothelial cells. Sci Rep 2017, 7: 39727.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Sakaguchi M, Murata H, Yamamoto KI, Ono T, Sakaguchi Y, Motoyama A, et al. TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. PLoS One 2011, 6: e23132.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Sousa MM, du Yan S, Fernandes R, Guimaraes A, Stern D, Saraiva MJ. Familial amyloid polyneuropathy: receptor for advanced glycation end products-dependent triggering of neuronal inflammatory and apoptotic pathways. J Neurosci 2001, 21: 7576–7586.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Ma WC, Rai V, Hudson BI, Song F, Schmidt AM, Barile GR. RAGE binds C1q and enhances C1q-mediated phagocytosis. Cell Immunol 2012, 274: 72–82.

    Article  PubMed  CAS  Google Scholar 

  21. Sturchler E, Galichet A, Weibel M, Leclerc E, Heizmann CW. Site-specific blockade of RAGE-Vd prevents amyloid-beta oligomer neurotoxicity. J Neurosci 2008, 28: 5149–5158.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kim OY, Song J. The importance of BDNF and RAGE in diabetes-induced dementia. Pharmacol Res 2020, 160: 105083.

    Article  PubMed  CAS  Google Scholar 

  23. Chavakis T, Bierhaus A, Al-Fakhri N, Schneider D, Witte S, Linn T, et al. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med 2003, 198: 1507–1515.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Sirois CM, Jin TC, Miller AL, Bertheloot D, Nakamura H, Horvath GL, et al. RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. J Exp Med 2013, 210: 2447–2463.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. He M, Kubo H, Morimoto K, Fujino N, Suzuki T, Takahasi T, et al. Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells. EMBO Rep 2011, 12: 358–364.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Ray R, Jangde N, Singh SK, Sinha S, Rai V. Lysophosphatidic acid-RAGE axis promotes lung and mammary oncogenesis via protein kinase B and regulating tumor microenvironment. Cell Commun Signal 2020, 18: 170.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Grunwald MS, Ligabue-Braun R, Souza CS, Heimfarth L, Verli H, Gelain DP, et al. Putative model for heat shock protein 70 complexation with receptor of advanced glycation end products through fluorescence proximity assays and normal mode analyses. Cell Stress Chaperones 2017, 22: 99–111.

    Article  PubMed  CAS  Google Scholar 

  28. Consortium U. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res 2021, 49: D480–D489.

    Article  CAS  Google Scholar 

  29. López Y, Nakai KT, Patil A. HitPredict version 4: Comprehensive reliability scoring of physical protein-protein interactions from more than 100 species. Database (Oxford) 2015, 2015: bav117.

  30. Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, et al. Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a Notch homolog, human counterpart of mouse mammary tumor gene int-3. Genomics 1994, 23: 408–419.

    Article  PubMed  CAS  Google Scholar 

  31. Serveaux-Dancer M, Jabaudon M, Creveaux I, Belville C, Blondonnet R, Gross C, et al. Pathological implications of receptor for advanced glycation end-product (AGER) gene polymorphism. Dis Markers 2019, 2019: 2067353.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Hudson BI, Carter AM, Harja E, Kalea AZ, Arriero M, Yang H, et al. Identification, classification, and expression of RAGE gene splice variants. FASEB J 2008, 22: 1572–1580.

    Article  PubMed  CAS  Google Scholar 

  33. Schmidt AM, Stern DM. Receptor for age (RAGE) is a gene within the major histocompatibility class III region: implications for host response mechanisms in homeostasis and chronic disease. Front Biosci 2001, 6: D1151–D1160.

    PubMed  CAS  Google Scholar 

  34. MacLean M, Derk J, Ruiz HH, Juranek JK, Ramasamy R, Schmidt AM. The receptor for advanced glycation end products (RAGE) and DIAPH1: implications for vascular and neuroinflammatory dysfunction in disorders of the central nervous system. Neurochem Int 2019, 126: 154–164.

    Article  PubMed  CAS  Google Scholar 

  35. Kalea AZ, Schmidt AM, Hudson BI. Alternative splicing of RAGE: Roles in biology and disease. Front Biosci (Landmark Ed) 2011, 16: 2756–2770.

    Article  CAS  Google Scholar 

  36. Allmen EUV, Koch M, Fritz G, Legler DF. V domain of RAGE interacts with AGEs on prostate carcinoma cells. Prostate 2008, 68: 748–758.

    Article  PubMed  CAS  Google Scholar 

  37. Leclerc E, Fritz G, Vetter SW, Heizmann CW. Binding of S100 proteins to RAGE: an update. Biochim Biophys Acta 2009, 1793: 993–1007.

    Article  PubMed  CAS  Google Scholar 

  38. Lee EJ, Park JH. Receptor for advanced glycation endproducts (RAGE), its ligands, and soluble RAGE: potential biomarkers for diagnosis and therapeutic targets for human renal diseases. Genom Inform 2013, 11: 224–229.

    Article  Google Scholar 

  39. Huttunen HJ, Kuja-Panula J, Rauvala H. Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation. J Biol Chem 2002, 277: 38635–38646.

    Article  PubMed  CAS  Google Scholar 

  40. Huttunen HJ, Kuja-Panula J, Sorci G, Agneletti AL, Donato R, Rauvala H. Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. J Biol Chem 2000, 275: 40096–40105.

    Article  PubMed  CAS  Google Scholar 

  41. Riuzzi F, Sorci G, Sagheddu R, Chiappalupi S, Salvadori L, Donato R. RAGE in the pathophysiology of skeletal muscle. J Cachexia Sarcopenia Muscle 2018, 9: 1213–1234.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Egaña-Gorroño L, López-Díez R, Yepuri G, Ramirez LS, Reverdatto S, Gugger PF, et al. Receptor for advanced glycation end products (RAGE) and mechanisms and therapeutic opportunities in diabetes and cardiovascular disease: insights from human subjects and animal models. Front Cardiovasc Med 2020, 7: 37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Chou DKH, Zhang JH, Smith FI, McCaffery P, Jungalwala FB. Developmental expression of receptor for advanced glycation end products (RAGE), amphoterin and sulfoglucuronyl (HNK-1) carbohydrate in mouse cerebellum and their role in neurite outgrowth and cell migration. J Neurochem 2004, 90: 1389–1401.

    Article  PubMed  CAS  Google Scholar 

  44. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 1995, 270: 25752–25761.

    Article  PubMed  CAS  Google Scholar 

  45. Song J, Lee WT, Park KA, Lee JE. Receptor for advanced glycation end products (RAGE) and its ligands: focus on spinal cord injury. Int J Mol Sci 2014, 15: 13172–13191.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Businaro R, Leone S, Fabrizi C, Sorci G, Donato R, Lauro GM, et al. S100B protects LAN-5 neuroblastoma cells against Abeta amyloid-induced neurotoxicity via RAGE engagement at low doses but increases Abeta amyloid neurotoxicity at high doses. J Neurosci Res 2006, 83: 897–906.

    Article  PubMed  CAS  Google Scholar 

  47. Huttunen HJ, Fages C, Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-κB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 1999, 274: 19919–19924.

    Article  PubMed  CAS  Google Scholar 

  48. Kierdorf K, Fritz G. RAGE regulation and signaling in inflammation and beyond. J Leukoc Biol 2013, 94: 55–68.

    Article  PubMed  CAS  Google Scholar 

  49. Sorci G, Riuzzi F, Giambanco I, Donato R. RAGE in tissue homeostasis, repair and regeneration. Biochim Biophys Acta 2013, 1833: 101–109.

    Article  PubMed  CAS  Google Scholar 

  50. Kim J, Wan CK, O’Carroll SJ, Shaikh SB, Nicholson LFB. The role of receptor for advanced glycation end products (RAGE) in neuronal differentiation. J Neurosci Res 2012, 90: 1136–1147.

    Article  PubMed  CAS  Google Scholar 

  51. Wang LY, Li ST, Jungalwala FB. Receptor for advanced glycation end products (RAGE) mediates neuronal differentiation and neurite outgrowth. J Neurosci Res 2008, 86: 1254–1266.

    Article  PubMed  CAS  Google Scholar 

  52. Piras S, Furfaro AL, Piccini A, Passalacqua M, Borghi R, Carminati E, et al. Monomeric Aβ1-42 and RAGE: key players in neuronal differentiation. Neurobiol Aging 2014, 35: 1301–1308.

    Article  PubMed  CAS  Google Scholar 

  53. Meneghini V, Francese MT, Carraro L, Grilli M. A novel role for the receptor for advanced glycation end-products in neural progenitor cells derived from adult SubVentricular Zone. Mol Cell Neurosci 2010, 45: 139–150.

    Article  PubMed  CAS  Google Scholar 

  54. Rong LL, Yan SF, Wendt T, Hans D, Pachydaki S, Bucciarelli LG, et al. RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways. FASEB J 2004, 18: 1818–1825.

    Article  PubMed  CAS  Google Scholar 

  55. Saleh A, Smith DR, Tessler L, Mateo AR, Martens C, Schartner E, et al. Receptor for advanced glycation end-products (RAGE) activates divergent signaling pathways to augment neurite outgrowth of adult sensory neurons. Exp Neurol 2013, 249: 149–159.

    Article  PubMed  CAS  Google Scholar 

  56. Wang HY, Mei XF, Cao Y, Liu C, Zhao ZM, Guo ZP, et al. HMGB1/Advanced Glycation End Products (RAGE) does not aggravate inflammation but promote endogenous neural stem cells differentiation in spinal cord injury. Sci Rep 2017, 7: 10332.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Sbai O, Devi TS, Melone MAB, Feron F, Khrestchatisky M, Singh LP, et al. RAGE-TXNIP axis is required for S100B-promoted Schwann cell migration, fibronectin expression and cytokine secretion. J Cell Sci 2010, 123: 4332–4339.

    Article  PubMed  CAS  Google Scholar 

  58. Tóbon-Velasco JC, Cuevas E, Torres-Ramos MA. Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress. CNS Neurol Disord Drug Targets 2014, 13: 1615–1626.

    Article  PubMed  CAS  Google Scholar 

  59. Daffu G, del Pozo CH, O’Shea KM, Ananthakrishnan R, Ramasamy R, Schmidt AM. Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond. Int J Mol Sci 2013, 14: 19891–19910.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Kalea AZ, Reiniger N, Yang H, Arriero M, Schmidt AM, Hudson BI. Alternative splicing of the murine receptor for advanced glycation end-products (RAGE) gene. FASEB J 2009, 6: 1766–1774.

    Article  CAS  Google Scholar 

  61. Ray R, Juranek JK, Rai V. RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis. Neurosci Biobehav Rev 2016, 62: 48–55.

    Article  PubMed  CAS  Google Scholar 

  62. Hudson BI, Lippman ME. Targeting RAGE signaling in inflammatory disease. Annu Rev Med 2018, 69: 349–364.

    Article  PubMed  CAS  Google Scholar 

  63. Corica D, Aversa T, Ruggeri RM, Cristani M, Alibrandi A, Pepe G, et al. Could AGE/RAGE-related oxidative homeostasis dysregulation enhance susceptibility to pathogenesis of cardio-metabolic complications in childhood obesity? Front Endocrinol (Lausanne) 2019, 10: 426.

    Article  PubMed Central  Google Scholar 

  64. Davis KE, Prasad C, Vijayagopal P, Juma S, Imrhan V. Advanced glycation end products, inflammation, and chronic metabolic diseases: links in a chain? Crit Rev Food Sci Nutr 2016, 56: 989–998.

    Article  PubMed  CAS  Google Scholar 

  65. Derk J, MacLean M, Juranek J, Schmidt AM. The receptor for advanced glycation endproducts (RAGE) and mediation of inflammatory neurodegeneration. J Alzheimers Dis Parkinsonism 2018, 8: 421.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Juranek J, Ray R, Banach M, Rai V. Receptor for advanced glycation end-products in neurodegenerative diseases. Rev Neurosci 2015, 26: 691–698.

    Article  PubMed  Google Scholar 

  67. Clynes R, Moser B, Yan SF, Ramasamy R, Herold K, Schmidt AM. Receptor for AGE (RAGE): weaving tangled webs within the inflammatory response. Curr Mol Med 2007, 7: 743–751.

    Article  PubMed  CAS  Google Scholar 

  68. Mitchell JD, Borasio GD. Amyotrophic lateral sclerosis. Lancet 2007, 369: 2031–2041.

    Article  PubMed  CAS  Google Scholar 

  69. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001, 344: 1688–1700.

    Article  PubMed  CAS  Google Scholar 

  70. Richardson K, Allen SP, Mortiboys H, Grierson AJ, Wharton SB, Ince PG, et al. The effect of SOD1 mutation on cellular bioenergetic profile and viability in response to oxidative stress and influence of mutation-type. PLoS One 2013, 8: e68256.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Casula M, Iyer AM, Spliet WGM, Anink JJ, Steentjes K, Sta M, et al. Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue. Neuroscience 2011, 179: 233–243.

    Article  PubMed  CAS  Google Scholar 

  72. Lo Coco D, Veglianese P, Allievi E, Bendotti C. 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 2007, 412: 73–77.

    Article  PubMed  CAS  Google Scholar 

  73. Hoyaux D, Boom A, van den Bosch L, Belot N, Martin JJ, Heizmann CW, et al. S100A6 overexpression within astrocytes associated with impaired axons from both ALS mouse model and human patients. J Neuropathol Exp Neurol 2002, 61: 736–744.

    Article  PubMed  CAS  Google Scholar 

  74. Hoyaux D, Alao J, Fuchs J, Kiss R, Keller B, Heizmann CW, et al. S100A6, a calcium- and zinc-binding protein, is overexpressed in SOD1 mutant mice, a model for amyotrophic lateral sclerosis. Biochim Biophys Acta 2000, 1498: 264–272.

    Article  PubMed  CAS  Google Scholar 

  75. Kamo H, Haebara H, Akiguchi I, Kameyama M, Kimura H, McGeer PL. A distinctive distribution of reactive astroglia in the precentral cortex in amyotrophic lateral sclerosis. Acta Neuropathol 1987, 74: 33–38.

    Article  PubMed  CAS  Google Scholar 

  76. Kawaguchi M, Shibata N, Horiuchi S, Kobayashi M. Glyoxal inactivates glutamate transporter-1 in cultured rat astrocytes. Neuropathology 2005, 25: 27–36.

    Article  PubMed  Google Scholar 

  77. Kato S, Horiuchi S, Liu J, Cleveland DW, Shibata N, Nakashima K, et al. Advanced glycation endproduct-modified superoxide dismutase-1 (SOD1)-positive inclusions are common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutations and transgenic mice expressing human SOD1 with a G85R mutation. Acta Neuropathol 2000, 100: 490–505.

    Article  PubMed  CAS  Google Scholar 

  78. Shibata N, Hirano A, Kato S, Nagai R, Horiuchi S, Komori T, et al. Advanced glycation endproducts are deposited in neuronal hyaline inclusions: a study on familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. Acta Neuropathol 1999, 97: 240–246.

    Article  PubMed  CAS  Google Scholar 

  79. Ding QX, Keller JN. Evaluation of rage isoforms, ligands, and signaling in the brain. Biochim Biophys Acta 2005, 1746: 18–27.

    Article  PubMed  CAS  Google Scholar 

  80. Lee JD, McDonald TS, Fung JNT, Woodruff TM. Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1 G93A mouse model of amyotrophic lateral sclerosis. Mol Neurobiol 2020, 57: 4143–4155.

    Article  PubMed  CAS  Google Scholar 

  81. Ma L, Sun P, Zhang JC, Zhang Q, Yao SL. Proinflammatory effects of S100A8/A9 via TLR4 and RAGE signaling pathways in BV-2 microglial cells. Int J Mol Med 2017, 40: 31–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Sternberg Z, Chiotti A, Tario J, Chichelli T, Patel N, Chadha K, et al. Reduced expression of membrane-bound (m)RAGE is a biomarker of multiple sclerosis disease progression. Immunobiology 2016, 221: 193–198.

    Article  PubMed  CAS  Google Scholar 

  83. Santos G, Barateiro A, Brites D, Fernandes A. S100B impairs oligodendrogenesis and myelin repair following demyelination through RAGE engagement. Front Cell Neurosci 2020, 14: 279.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Rahimi M, Aghabozorg Afjeh SS, Omrani MD, Arsang-Jang S, Ganji M, Noroozi R, et al. Soluble receptor for advanced glycation end products (sRAGE) is up-regulated in multiple sclerosis patients treated with interferon β-1a. Cell Physiol Biochem 2018, 46: 561–567.

    Article  PubMed  CAS  Google Scholar 

  85. Wetzels S, Vanmierlo T, Scheijen JLJM, van Horssen J, Amor S, Somers V, et al. Methylglyoxal-derived advanced glycation endproducts accumulate in multiple sclerosis lesions. Front Immunol 2019, 10: 855.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Xiao YF, Sun Y, Liu W, Zeng FF, Shi JY, Li J, et al. HMGB1 promotes the release of sonic hedgehog from astrocytes. Front Immunol 2021, 12: 584097.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Brás IC, König A, Outeiro TF. Glycation in Huntington’s disease: a possible modifier and target for intervention. J Huntingtons Dis 2019, 8: 245–256.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Kim J, Waldvogel HJ, Faull RLM, Curtis MA, Nicholson LFB. The RAGE receptor and its ligands are highly expressed in astrocytes in a grade-dependant manner in the striatum and subependymal layer in Huntington’s disease. J Neurochem 2015, 134: 927–942.

    Article  PubMed  CAS  Google Scholar 

  89. Son S, Bowie LE, Maiuri T, Hung CLK, Desmond CR, Xia JR, et al. High-mobility group box 1 links sensing of reactive oxygen species by huntingtin to its nuclear entry. J Biol Chem 2019, 294: 1915–1923.

    Article  PubMed  CAS  Google Scholar 

  90. Deane R, Yan SD, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, et al. RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 2003, 9: 907–913.

    Article  PubMed  CAS  Google Scholar 

  91. Li M, Shang DS, Zhao WD, Tian L, Li B, Fang WG, et al. Amyloid beta interaction with receptor for advanced glycation end products up-regulates brain endothelial CCR5 expression and promotes T cells crossing the blood-brain barrier. J Immunol 2009, 182: 5778–5788.

    Article  PubMed  CAS  Google Scholar 

  92. Liu LP, Hong H, Liao JM, Wang TS, Wu J, Chen SS, et al. Upregulation of RAGE at the blood-brain barrier in streptozotocin-induced diabetic mice. Synapse 2009, 63: 636–642.

    Article  PubMed  CAS  Google Scholar 

  93. Fuller KNZ, Miranda ER, Thyfault JP, Morris JK, Haus JM. Metabolic derangements contribute to reduced sRAGE isoforms in subjects with Alzheimer’s disease. Mediators Inflamm 2018, 2018: 2061376.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Kong YY, Wang FS, Wang J, Liu CP, Zhou YP, Xu ZQ, et al. Pathological mechanisms linking diabetes mellitus and Alzheimer’s disease: The receptor for advanced glycation end products (RAGE). Front Aging Neurosci 2020, 12: 217.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Criscuolo C, Fontebasso V, Middei S, Stazi M, Ammassari-Teule M, Yan SS, et al. Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer’s disease mouse model. Sci Rep 2017, 7: 42370.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Son M, Oh S, Park H, Ahn H, Choi J, Kim H, et al. Protection against RAGE-mediated neuronal cell death by sRAGE-secreting human mesenchymal stem cells in 5xFAD transgenic mouse model. Brain Behav Immun 2017, 66: 347–358.

    Article  PubMed  CAS  Google Scholar 

  97. Gasparotto J, Ribeiro CT, Bortolin RC, Somensi N, Rabelo TK, Kunzler A, et al. Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA-induced dopaminergic denervation. Sci Rep 2017, 7: 8795.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Viana SD, Valero J, Rodrigues-Santos P, Couceiro P, Silva AM, Carvalho F, et al. Regulation of striatal astrocytic receptor for advanced glycation end-products variants in an early stage of experimental Parkinson’s disease. J Neurochem 2016, 138: 598–609.

    Article  PubMed  CAS  Google Scholar 

  99. Wang XL, Sun XX, Niu MY, Zhang XN, Wang J, Zhou C, et al. RAGE silencing ameliorates neuroinflammation by inhibition of p38-NF-κB signaling pathway in mouse model of Parkinson’s disease. Front Neurosci 2020, 14: 353.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Liu LP, Killoy KM, Vargas MR, Yamamoto Y, Pehar M. Effects of RAGE inhibition on the progression of the disease in hSOD1 G93A ALS mice. Pharmacol Res Perspect 2020, 8: e00636.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Serrano A, Donno C, Giannetti S, Perić M, Andjus P, D’Ambrosi N, et al. The astrocytic S100B protein with its receptor RAGE is aberrantly expressed in SOD1 G93A models, and its inhibition decreases the expression of proinflammatory genes. Mediators Inflamm 2017, 2017: 1626204.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Yamamoto Y, Liang MK, Munesue S, Deguchi K, Harashima A, Furuhara K, et al. Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice. Commun Biol 2019, 2: 76.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Yamamoto Y, Higashida H. RAGE regulates oxytocin transport into the brain. Commun Biol 2020, 3: 70.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Franklin TC, Wohleb ES, Zhang Y, Fogaça M, Hare B, Duman RS. Persistent increase in microglial RAGE contributes to chronic stress-induced priming of depressive-like behavior. Biol Psychiatry 2018, 83: 50–60.

    Article  PubMed  CAS  Google Scholar 

  105. Fu JW, Zuo X, Yin JW, Luo XD, Li Z, Lin JD, et al. Association of polymorphisms of the receptor for advanced glycation endproducts gene with schizophrenia in a Han Chinese population. Biomed Res Int 2017, 2017: 6379639.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Miyashita M, Watanabe T, Ichikawa T, Toriumi K, Horiuchi Y, Kobori A, et al. The regulation of soluble receptor for AGEs contributes to carbonyl stress in schizophrenia. Biochem Biophys Res Commun 2016, 479: 447–452.

    Article  PubMed  CAS  Google Scholar 

  107. Zglejc-Waszak K, Mukherjee K, Juranek JK. The cross-talk between RAGE and DIAPH1 in neurological complications of diabetes: a review. Eur J Neurosci 2021, 54: 5982–5999.

    Article  PubMed  CAS  Google Scholar 

  108. Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol 2021, 17: 400–420.

    Article  PubMed  Google Scholar 

  109. Juranek JK, Kothary P, Mehra A, Hays A, Brannagan THI, Schmidt AM. Increased expression of the receptor for advanced glycation end-products in human peripheral neuropathies. Brain Behav 2013, 3: 701–709.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Juranek JK, Geddis MS, Song F, Zhang JH, Garcia J, Rosario R, et al. RAGE deficiency improves postinjury sciatic nerve regeneration in type 1 diabetic mice. Diabetes 2013, 62: 931–943.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Juranek JK, Aleshin A, Rattigan EM, Johnson L, Qu W, Song F, et al. Morphological changes and immunohistochemical expression of RAGE and its ligands in the sciatic nerve of hyperglycemic pig (Sus scrofa). Biochem Insights 2010, 2010: 47–59.

    PubMed  Google Scholar 

  112. Lukic IK, Humpert PM, Nawroth PP, Bierhaus A. The RAGE pathway: activation and perpetuation in the pathogenesis of diabetic neuropathy. Ann N Y Acad Sci 2008, 1126: 76–80.

    Article  PubMed  CAS  Google Scholar 

  113. Bekircan-Kurt CE, Tan E, Erdem ÖS. The activation of RAGE and NF-κB in nerve biopsies of patients with axonal and vasculitic neuropathy. Noro Psikiyatr Ars 2015, 52: 279–282.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Klein I, Lehmann HC. Pathomechanisms of paclitaxel-induced peripheral neuropathy. Toxics 2021, 9: 229.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Sekiguchi F, Domoto R, Nakashima K, Yamasoba D, Yamanishi H, Tsubota M, et al. Paclitaxel-induced HMGB1 release from macrophages and its implication for peripheral neuropathy in mice: Evidence for a neuroimmune crosstalk. Neuropharmacology 2018, 141: 201–213.

    Article  PubMed  CAS  Google Scholar 

  116. Tsubota M, Miyazaki T, Ikeda Y, Hayashi Y, Aokiba Y, Tomita S, et al. Caspase-dependent HMGB1 release from macrophages participates in peripheral neuropathy caused by bortezomib, a proteasome-inhibiting chemotherapeutic agent, in mice. Cells 2021, 10: 2550.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Wafa A, El-Nahas M, Al Biaumy A, Mansour Y. Study of advanced glycation endproducts and their receptors in Egyptian type 2 diabetic individuals with peripheral neuropathy. Egypt J Obes Diabet Endocrinol 2017, 3: 15.

    Article  Google Scholar 

  118. Lam D, Momeni Z, Theaker M, Jagadeeshan S, Yamamoto Y, Ianowski JP, et al. RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose. PLoS One 2018, 13: e0193312.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Bestall SM, Hulse RP, Blackley Z, Swift M, Ved N, Paton K, et al. Sensory neuronal sensitisation occurs through HMGB-1-RAGE and TRPV1 in high-glucose conditions. J Cell Sci 2018, 131: jcs215939.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Osonoi S, Mizukami H, Ogasawara S, Takahashi K, Sango K, Yagihashi S. Suppression of neuropathy development in diabetic rage-deficient mice is associated with absence of M1/M2 macrophage skewing in the sciatic nerve. Diabetes 2018, https://doi.org/10.2337/db18-575-P.

    Article  Google Scholar 

  121. Wautier JL, Guillausseau PJ. Advanced glycation end products, their receptors and diabetic angiopathy. Diabet Metab 2001, 27: 535–542.

    CAS  Google Scholar 

  122. Li XN, Yang HQ, Ouyang Q, Liu FT, Li J, Xiang ZH, et al. Enhanced RAGE expression in the dorsal root ganglion may contribute to neuropathic pain induced by spinal nerve ligation in rats. Pain Med 2016, 17: 803–812.

    PubMed  Google Scholar 

  123. Solmaz V, Kaya M, Uslu FB, Atasoy O, Erbaş O. Papaverine has therapeutic potential for Sepsis-induced neuropathy in rats, possibly via the modulation of HMGB1-RAGE axis and its antioxidant prosperities. J Invest Surg 2022, 35: 7–13. https://doi.org/10.1080/08941939.2020.1809751.

    Article  Google Scholar 

  124. Wang MY, Ross-Cisneros FN, Aggarwal D, Liang CY, Sadun AA. Receptor for advanced glycation end products is upregulated in optic neuropathy of Alzheimer’s disease. Acta Neuropathol 2009, 118: 381–389.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Tezel G, Luo C, Yang XJ. Accelerated aging in glaucoma: Immunohistochemical assessment of advanced glycation end products in the human retina and optic nerve head. Invest Ophthalmol Vis Sci 2007, 48: 1201–1211.

    Article  PubMed  Google Scholar 

  126. Łacheta D, Poślednik KB, Czerwaty K, Ludwig N, Molińska-Glura M, Kantor I, et al. RAGE and HMGB1 expression in orbital tissue microenvironment in Graves’ ophthalmopathy. Mediators Inflamm 2021, 2021: 8891324.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Hudson BI, Stickland MH, Futers TS, Grant PJ. Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy. Diabetes 2001, 50: 1505–1511.

    Article  PubMed  CAS  Google Scholar 

  128. Hammes HP, Hoerauf H, Alt A, Schleicher E, Clausen JT, Bretzel RG, et al. N(Epsilon)(carboxymethyl)lysin and the AGE receptor RAGE colocalize in age-related macular degeneration. Invest Ophthalmol Vis Sci 1999, 40: 1855–1859.

    PubMed  CAS  Google Scholar 

  129. Sakatani S, Yamada K, Homma C, Munesue S, Yamamoto Y, Yamamoto H, et al. Deletion of RAGE causes hyperactivity and increased sensitivity to auditory stimuli in mice. PLoS One 2009, 4: e8309.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Xing Y, Ji QH, Li XM, Ming J, Zhang NN, Zha DJ, et al. Asiaticoside protects cochlear hair cells from high glucose-induced oxidative stress via suppressing AGEs/RAGE/NF-κB pathway. Biomed Pharmacother 2017, 86: 531–536.

    Article  PubMed  CAS  Google Scholar 

  131. Lee CH, Kim KW, Lee DH, Lee SM, Kim SY. Overexpression of the receptor for advanced glycation end-products in the auditory cortex of rats with noise-induced hearing loss. BMC Neurosci 2021, 22: 38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Gao X, Lin C, Lu L, Liang G, Chen Z, Zhang X. RAGE, NF-kappaB, p21 expressions in mouse spiral ganglion cells. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2014, 28: 265–268.

    PubMed  CAS  Google Scholar 

  133. Angelopoulou E, Paudel YN, Piperi C. Unraveling the role of receptor for advanced glycation end products (RAGE) and its ligands in myasthenia gravis. ACS Chem Neurosci 2020, 11: 663–673.

    Article  PubMed  CAS  Google Scholar 

  134. Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, et al. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021, 49: D605–D612.

    Article  PubMed  CAS  Google Scholar 

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  1. Judyta Juranek and Konark Mukherjee have contributed equally to this work.

Authors and Affiliations

  1. Department of Human Physiology and Pathophysiology, School of Medicine, University of Warmia and Mazury, 10-085, Olsztyn, Poland

    Judyta Juranek, Bernard Kordas, Agnieszka Korytko & Kamila Zglejc-Waszak

  2. Fralin Biomedical Research Institute at VTC, Virginia Tech, Blacksburg, VA, 24016, USA

    Konark Mukherjee

  3. Department of Animal Anatomy, Faculty of Veterinary Medicine, University of Warmia and Mazury, 10-719, Olsztyn, Poland

    Michał Załęcki

  4. Department of Materials and Machines Technology, Faculty of Technical Sciences, University of Warmia and Mazury, 10-719, Olsztyn, Poland

    Jarosław Szuszkiewicz

  5. Department of Neurology, Collegium Medicum, Jagiellonian University, 31-008, Kraków, Poland

    Marta Banach

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  1. Judyta Juranek
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Juranek, J., Mukherjee, K., Kordas, B. et al. Role of RAGE in the Pathogenesis of Neurological Disorders. Neurosci. Bull. 38, 1248–1262 (2022). https://doi.org/10.1007/s12264-022-00878-x

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