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Licensed Unlicensed Requires Authentication Published by De Gruyter July 30, 2015

Receptor for advanced glycation end-products in neurodegenerative diseases

  • Judyta Juranek EMAIL logo , Rashmi Ray , Marta Banach and Vivek Rai EMAIL logo

Abstract

This review, for the first time, aims to summarize the current knowledge in the emerging field of RAGE (receptor for advanced glycation end-products) studies in neurodegeneration and neurodegenerative diseases. RAGE, a member of the multiligand cell surface immunoglobulin family, has been implicated in numerous pathological conditions – from diabetes and cardiovascular diseases to tumors and neurodegenerative disorders, such as Alzheimer’s disease, familial amyloid polyneuropathy, diabetic neuropathy, Parkinson’s disease, and Huntington’s disease. Until now, the detailed mechanisms of the contribution of RAGE to neurodegeneration remain elusive; however, mounting evidence suggests that its detrimental actions are triggered by its ligand interactions and contribute to increased neuroinflammation, neuronal degeneration, and apoptosis. Deciphering the role of RAGE in neurodegenerative disorders will be a milestone in our basic understanding of the mechanisms involved in the pathogenesis of neurodegeneration, helping to delineate molecular links between complex RAGE signaling pathways and neuronal dysfunction and neurodegeneration.


Corresponding authors: Judyta Juranek, Department of Medicine, New York University Langone Medical Center, New York, NY, 10016, USA; and Faculty of Medical Sciences, University of Warmia and Mazury, Warszawska 30, 10-082 Olsztyn, Poland, e-mail: ; and Vivek Rai, Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, India, e-mail:
aThese authors contributed equally to the work.

References

Anzilotti, S., Giampa, C., Laurenti, D., Perrone, L., Bernardi, G., Melone, M.A., and Fusco, F.R. (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.2011.01.009Search in Google Scholar

Bierhaus, A., Schiekofer, S., Schwaninger, M., Andrassy, M., Humpert, P.M., Chen, J., Hong, M., Luther, T., Henle, T., Klöting, I., et al. (2001). Diabetes-associated sustained activation of the transcription factor nuclear factor-κB. Diabetes 50, 2792–2808.10.2337/diabetes.50.12.2792Search in Google Scholar

Bekircan-Kurt, C.E., Uçeyler, N., and Sommer, C. (2014). Cutaneous activation of RAGE in nonsystemic vasculitic and diabetic neuropathy. Muscle Nerve 50, 377–383.10.1002/mus.24164Search in Google Scholar

Braak, H., Del, T.K., Rub, U., de Vos, R.A., Jansen, S.E.N., and Braak, E. (2003). Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211.10.1016/S0197-4580(02)00065-9Search in Google Scholar

Casula, M., Iyer, A.M., Spliet, W.G., Anink, J.J., Steentjes, K., Sta, M., Troost, D., and Aronica, E. (2011). Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue. Neuroscience 179, 233–243.10.1016/j.neuroscience.2011.02.001Search in Google Scholar PubMed

Cho, H.J., Son, S.M., Jin, S.M., Hong, H.S., Shin, D.H., Kim, S.J., Huh, K., and Mook-Jung, I. (2009). RAGE regulates BACE1 and Aβ generation via NFAT1 activation in Alzheimer’s disease animal model. FASEB J. 23, 2639–2649.10.1096/fj.08-126383Search in Google Scholar PubMed

Chou, S.M., Wang, H.S., Taniguchi, A., and Bucala, R. (1998). Advanced glycation endproducts in neurofilament conglomeration of motoneurons in familial and sporadic amyotrophic lateral sclerosis. Mol. Med. 4, 324–332.10.1007/BF03401739Search in Google Scholar

da Costa, G., Gomes, R.A., Guerreiro, A., Mateus, E., Monteiro, E., Barroso, E., Coelho, A.V., Freire, A.P., and Cordeiro, C. (2011). Beyond genetic factors in familial amyloidotic polyneuropathy: protein glycation and the loss of fibrinogen’s chaperone activity. PLoS One 6, e24850.10.1371/journal.pone.0024850Search in Google Scholar PubMed PubMed Central

Dalfo, E., Portero-Otin, M., Ayala, V., Martinez, A., Pamplona, R., and Ferrer, I. (2005). Evidence of oxidative stress in the neocortex in incidental Lewy body disease. J. Neuropathol. Exp. Neurol. 64, 816–830.10.1097/01.jnen.0000179050.54522.5aSearch in Google Scholar PubMed

Ding, Q. and Keller, J.N. (2005). Evaluation of RAGE isoforms, ligands, and signaling in the brain. Biochim. Biophys. Acta 1746, 18–27.10.1016/j.bbamcr.2005.08.006Search in Google Scholar PubMed

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)00046-2Search in Google Scholar

Franciosi, S., Shim, Y., Lau, M., Hayden, M.R., and Leavitt, B.R. (2013). A systematic review and meta-analysis of clinical variables used in Huntington disease research. Mov. Disord. 28, 1987–1994.10.1002/mds.25663Search in Google Scholar

Freixes, M., Rodriguez, A., Dalfo, E., and Ferrer, I. (2006). Oxidation, glycoxidation, lipoxidation, nitration, and responses to oxidative stress in the cerebral cortex in Creutzfeldt-Jakob disease. Neurobiol. Aging 27, 1807–1815.10.1016/j.neurobiolaging.2005.10.006Search in Google Scholar

Gao, J., Teng, J., Liu, H., Han, X., Chen, B., and Xie, A. (2014). Association of RAGE gene polymorphisms with sporadic Parkinson’s disease in Chinese Han population. Neurosci. Lett. 559, 158–162.10.1016/j.neulet.2013.11.038Search in Google Scholar

Haslbeck, K.M., Neundörfer, B., Schlötzer-Schrehardtt, U., Bierhaus, A., Schleicher, E., Pauli, E., Haslbeck, M., Hecht, M., Nawroth, P., and Heuss, D. (2007). Activation of the RAGE pathway: a general mechanism in the pathogenesis of polyneuropathies? Neurol. Res. 29, 103–110.10.1179/174313206X152564Search in Google Scholar

Hofmann, M.A., Drury, S., Fu, C., Qu, W., Taguchi, A., Lu, Y., Avila, C., Kambham, N., Bierhaus, A., Nawroth, P., et al. (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)80801-6Search in Google Scholar

Hughes, R.A. (2002). Peripheral neuropathy. Br. Med. J. 324, 466–469.10.1136/bmj.324.7335.466Search in Google Scholar PubMed PubMed Central

Huttunen, H.J., Kuja-Panula, J., Sorci, G., Agneletti, A.L., Donato, R., and 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.M006993200Search in Google Scholar PubMed

Huttunen, H.J., Kuja-Panula, J., and Rauvala, H. (2002). Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during neuronal differentiation. J. Biol. Chem. 277, 38635–38646.10.1074/jbc.M202515200Search in Google Scholar PubMed

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.xSearch in Google Scholar PubMed

Jankovic, J. (2008). Parkinson’s disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatry 79, 368–376.10.1136/jnnp.2007.131045Search in Google Scholar PubMed

Juranek, J.K., Aleshin, A., Rattigan, E.M., Johnson, L., Qu, W., Song, F., Ananthakrishnan, R., Quadri, N., Yan, S.D., Ramasamy, R., et al. (2010). Morphological changes and immunohistochemical expression of RAGE and its ligands in the sciatic nerve of hyperglycemic pig (Sus scrofa). Biochem. Insights 2010, 47–59.10.4137/BCI.S5340Search in Google Scholar PubMed PubMed Central

Juranek, J.K., Geddis, M.S., Song, F., Zhang, J., Garcia, J., Rosario, R., Yan, S.F., Brannagan, T.H., and Schmidt, A.M. (2013a). RAGE deficiency improves postinjury sciatic nerve regeneration in type 1 diabetic mice. Diabetes 62, 931–943.10.2337/db12-0632Search in Google Scholar PubMed PubMed Central

Juranek, J.K., Kothary, P., Mehra, A., Hays, A., Brannagan, T.H. 3rd, and 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/brb3.176Search in Google Scholar PubMed PubMed Central

Kim, S.W., Lim, C.M., Kim, J.B., Shin, J.H., Lee, S., Lee, M., and Lee, J.K. (2011). Extracellular HMGB1 released by NMDA treatment confers neuronal apoptosis via RAGE-p38 MAPK/ERK signaling pathway. Neurotoxicol. Res. 20, 159–169.10.1007/s12640-010-9231-xSearch in Google Scholar PubMed

Lee, D., Park, C.W., Paik, S.R., and Choi, K.Y. (2009). The modification of α-synuclein by dicarbonyl compounds inhibits its fibril-forming process. Biochim. Biophys. Acta 1794, 421–430.10.1016/j.bbapap.2008.11.016Search in Google Scholar PubMed

Lee, J.J., Wang, P.W., Yang, I.H., Wu, C.L., and Chuang, J.H. (2015). Amyloid-β mediates the receptor of advanced glycation end product-induced pro-inflammatory response via Toll-like receptor 4 signaling pathway in retinal ganglion cell line RGC-5. Int. J. Biochem. Cell. Biol. 64, 1–10.10.1016/j.biocel.2015.03.002Search in Google Scholar PubMed

Li, J. and Schmidt, A.M. (1997). Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J. Biol. Chem. 272, 16498–16506.10.1074/jbc.272.26.16498Search in Google Scholar PubMed

Liu, R., Wu, C.X., Zhou, D., Yang, F., Tian, S., Zhang, L., Zhang, T.T., and Du, G.H. (2012). Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis. BMC Med. 10, 105.10.1186/1741-7015-10-105Search in Google Scholar PubMed PubMed Central

Lue, L.-F., Walker, D.G., Brachova, L., Beach, T.G., Rogers, J., Schmidt, A.M., Stern, D.M., and Yan, S.D. (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.2001.7732Search in Google Scholar PubMed

Ma, L. and 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.2004.05.052Search in Google Scholar

Mackic, J.B., Stins, M., McComb, J.G., Calero, M., Ghiso, J., Kim, K.S., Yan, S..D, Stern, D., Schmidt, A.M., Frangione, B., et al. (1998). Human blood-brain barrier receptors for Alzheimer’s amyloid-β 1-40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. J. Clin. Invest. 102, 734–743.10.1172/JCI2029Search in Google Scholar

Matrone, C., Djelloul, M., Taglialatela, G., and Perrone, L. (2015). Inflammatory risk factors and pathologies promoting Alzheimer’s disease progression: is RAGE the key? Histol. Histopathol. 30, 125–139.Search in Google Scholar

Matsunaga, N., Anan, I., Forsgren, S., Nagai, R., Rosenberg, P., Horiuchi, S., Ando, Y., and Suhr, O.B. (2002). Advanced glycation end products (AGE) and the receptor for AGE are present in gastrointestinal tract of familial amyloidotic polyneuropathy patients but do not induce NF-κB activation. Acta Neuropathol. 104, 441–447.10.1007/s00401-002-0574-0Search in Google Scholar

Mattson, M.P. and Camandola, S. (2001). NF-kappaB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest. 107, 247–254.10.1172/JCI11916Search in Google Scholar

Neeper, M., Schmidt, A.M., Brett, J., Yan, S.D., Wang, F., Pan, Y.C., Elliston, K., Stern, D., and Shaw, A. (1992). Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J. Biol. Chem. 267, 14998–15004.10.1016/S0021-9258(18)42138-2Search in Google Scholar

Outeiro, T.F., Kontopoulos, E., Altmann, S.M., Kufareva, I., Strathearn, K.E., Amore, A.M., Volk, C.B., Maxwell, M.M., Rochet, J.C., McLean, P.J., et al. (2007). Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317, 516–519.10.1126/science.1143780Search in Google Scholar PubMed

Padmaraju, V., Bhaskar, J.J., Prasada, R.U.J., Salimath, P.V., and Rao, K.S. (2011). Role of advanced glycation on aggregation and DNA binding properties of α-synuclein. J. Alzheimers Dis. 24, 211–221.10.3233/JAD-2011-101965Search in Google Scholar PubMed

Park, S.Y., Kim, Y.A., Hong, Y.H., Moon, M.K., Koo, B.K., and Kim, T.W. (2014). Up-regulation of the receptor for advanced glycation end products in the skin biopsy specimens of patients with severe diabetic neuropathy. J. Clin. Neurol. 10, 334–341.10.3988/jcn.2014.10.4.334Search in Google Scholar PubMed PubMed Central

Piras, S., Furfaro, A.L., Piccini, A., Passalacqua, M., Borghi, R., Carminati, E., Parodi, A., Colombo, L., Salmona, M., Pronzato, M.A., et al. (2014). Monomeric Aβ1-42 and RAGE: key players in neuronal differentiation. Neurobiol. Aging 35, 1301–1308.10.1016/j.neurobiolaging.2014.01.002Search in Google Scholar PubMed

Ramasamy, R., Vannucci, S.J., Yan, S.S., Herold, K., Yan, S.F., and Schmidt, A.M. (2005). Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 15, 16R–28R.10.1093/glycob/cwi053Search in Google Scholar PubMed

Rong, L.L., Gooch, C., Szabolcs, M., Herold, K.C., Lalla, E., Hays, A.P., Yan, S.F., Yan, S.S., and Schmidt, A.M. (2005). RAGE: a journey from the complications of diabetes to disorders of the nervous system – striking a fine balance between injury and repair. Restor. Neurol. Neurosci. 23, 355–365.Search in Google Scholar

Sabbagh, M.N., Agro, A., Bell, J., Aisen, P.S., Schweizer, E., and Galasko, D. (2011). PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 25, 206–212.10.1097/WAD.0b013e318204b550Search in Google Scholar

Sajithlal, G., Huttunen, H., Rauvala, H., and Munch, G. (2002). Receptor for advanced glycation end products plays a more important role in cellular survival than in neurite outgrowth during retinoic acid-induced differentiation of neuroblastoma cells. J. Biol. Chem. 277, 6888–6897.10.1074/jbc.M107627200Search in Google Scholar

Saleh, A., Smith, D.R., Tessler, L., Mateo, A.R., Martens, C., Schartner, E., Van der Ploeg, R., Toth, C., Zochodne, D.W., and Fernyhough, P. (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.2013.08.018Search in Google Scholar

Saraiva, M.J., Birken, S., Costa, P.P., and Goodman, D.S. (1984). Family studies of the genetic abnormality in transthyretin (prealbumin) in Portuguese patients with familial amyloidotic polyneuropathy. Ann. NY Acad. Sci. 435, 86–100.10.1111/j.1749-6632.1984.tb13742.xSearch in Google Scholar

Sasaki, N., Takeuchi, M., Chowei, H., Kikuchi, S., Hayashi, Y., Nakano, N., Ikeda, H., Yamagishi, S., Kitamoto, T., Saito, T., et al. (2002). Advanced glycation end products (AGE) and their receptor (RAGE) in the brain of patients with Creutzfeldt-Jakob disease with prion plaques. Neurosci. Lett. 326, 117–120.10.1016/S0304-3940(02)00310-5Search in Google Scholar

Sathe, K., Maetzler, W., Lang, J.D., Mounsey, R.B., Fleckenstein, C., Martin, H.L., Schulte, C., Mustafa, S., Synofzik, M., Vukovic, Z., et al. (2012). S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-α pathway. Brain 135, 3336–3347.10.1093/brain/aws250Search in Google Scholar

Sbai, O., Devi, T.S., Melone, M.A., Feron, F., Khrestchatisky, M., Singh, L.P., and Perrone, L. (2010). RAGE-TXNIP axis is required for S100B-promoted Schwann cell migration, fibronectin expression and cytokine secretion. J. Cell. Sci. 123, 4332–4339.10.1242/jcs.074674Search in Google Scholar

Schmidt, A.M., Vianna, M., Gerlach, M., Brett, J., Ryan, J., Kao, J., Esposito, C., Hegarty, H., Hurley, W., Clauss, M., et al. (1992). Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. J. Biol. Chem. 267, 14987–14997.10.1016/S0021-9258(18)42137-0Search in Google Scholar

Shibata, N., Hirano, A., Hedley-Whyte, E.T., Dal Canto, M.C., Nagai, R., Uchida, K., Horiuchi, S., Kawaguchi, M., Yamamoto, T., and Kobayashi, M. (2002). Selective formation of certain advanced glycation end products in spinal cord astrocytes of humans and mice with superoxide dismutase-1 mutation. Acta Neuropathol. 104, 171–178.10.1007/s00401-002-0537-5Search in Google Scholar PubMed

Shorter, J. and Lindquist, S. (2005). Prions as adaptive conduits of memory and inheritance. Nat. Rev. Genet. 6, 435–450.10.1038/nrg1616Search in Google Scholar PubMed

Sousa, M.M., Yan, S.D., Stern, D., and Saraiva, M.J. (2000). Interaction of the receptor for advanced glycation end products (RAGE) with transthyretin triggers nuclear transcription factor κB (NF-κB) activation. Lab. Invest. 80, 1101–1110.10.1038/labinvest.3780116Search in Google Scholar PubMed

Taguchi, A., Blood, D.C., del Toro, G., Canet, A., Lee, D.C., Qu, W., Tanji, N., Lu, Y., Lalla, E., Fu, C., et al. (2000). Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405, 354–360.10.1038/35012626Search in Google Scholar PubMed

Takamiya, R., Takahashi, M., Myint, T., Park, Y.S., Miyazawa, N., Endo, T., Fujiwara, N., Sakiyama, H., Misonou, Y., Miyamoto, Y., et al. (2003). Glycation proceeds faster in mutated Cu, Zn-superoxide dismutases related to familial amyotrophic lateral sclerosis. FASEB J. 17, 938–940.10.1096/fj.02-0768fjeSearch in Google Scholar PubMed

Teismann, P., Sathe, K., Bierhaus, A., Leng, L., Martin, H.L., Bucala, R., Weigle, B., Nawroth, P.P., and Schulz, J.B. (2012). Receptor for advanced glycation endproducts (RAGE) deficiency protects against MPTP toxicity. Neurobiol. Aging 33, 2478–2490.10.1016/j.neurobiolaging.2011.12.006Search in Google Scholar PubMed PubMed Central

Toth, C., Rong, L.L., Yang, C., Martinez, J., Song, F., Ramji, N., Brussee, V., Liu, W., Durand, J., Nguyen, M.D., et al. (2008). Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy. Diabetes 57, 1002–1017.10.2337/db07-0339Search in Google Scholar PubMed

Wang, L., Li, S., and Jungalwala, F.B. (2008). Receptor for advanced glycation end products (RAGE) mediates neuronal differentiation and neurite outgrowth. J. Neurosci. Res. 86, 1254–1266.10.1002/jnr.21578Search in Google Scholar PubMed

Xu, Y., Toure, F., Qu, W., Lin, L., Song, F., Shen, X., Rosario, R., Garcia, J., Schmidt, A.M., and Yan, S.F. (2010). Advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling and up-regulation of Egr-1 in hypoxic macrophages. J. Biol. Chem. 285, 23233–23240.10.1074/jbc.M110.117457Search in Google Scholar PubMed PubMed Central

Yan, S.D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., et al. (1996). RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease. Nature 382, 685–691.10.1038/382685a0Search in Google Scholar PubMed

Yan, S.D., Zhu, H., Zhu, A., Golabek, A., Du, H., Roher, A., Yu, J., Soto, C., Schmidt, A.M., Stern, D., et al. (2000). Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat. Med. 6, 643–651.10.1038/76216Search in Google Scholar PubMed

Received: 2015-1-22
Accepted: 2015-4-19
Published Online: 2015-7-30
Published in Print: 2015-12-1

©2015 by De Gruyter

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