Amino Acids

, Volume 42, Issue 4, pp 1221–1236

Advanced glycation endproducts and their pathogenic roles in neurological disorders

  • Gerald Münch
  • Bernadette Westcott
  • Teresita Menini
  • Alejandro Gugliucci
Review Article


Glycation is implicated in neurological disorders. In some cases it plays a key role in the pathogenesis, in others it plays a co-adjuvant role or it appears as a consequence of degenerative changes and protein accumulation stemming from other pathways. In this work, we attempt to provide a concise, updated review of the major recent findings concerning glycation in neurological diseases. After a short introduction covering advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE), we will discuss the impact of glycation in central nervous system disorders including Alzheimer’s, Parkinson’s and Creutzfeldt–Jakob disease, as well as peripheral diabetic polyneuropathies. Therapies directed at lowering the concentrations of RAGE ligands including AGEs, blocking RAGE signaling, preventing oxidative stress or lowering methylglyoxal (MGO) levels may significantly decrease the development of AGE-related pathologies in patients with neurological disorders. Many drugs are on the pipeline and the future clinical trials will reveal if the promising results translate into clinical application.


Advanced glycation endproducts Methylglyoxal NF-kB Alzheimer’s disease Inflammation Diabetes 


  1. Ahmed N (2005) Advanced glycation endproducts—role in pathology of diabetic complications. Diabetes Res Clin Pract 67(1):3–21PubMedGoogle Scholar
  2. Ahmed N, Battah S, Karachalias N, Babaei-Jadidi R, Horanyi M, Baroti K, Hollan S, Thornalley PJ (2003) Increased formation of methylglyoxal and protein glycation, oxidation and nitrosation in triosephosphate isomerase deficiency. Biochim Biophys Acta 1639(2):121–132PubMedGoogle Scholar
  3. Andersson A, Covacu R, Sunnemark D, Danilov AI, Dal Bianco A, Khademi M, Wallstrom E, Lobell A, Brundin L, Lassmann H, Harris RA (2008) Pivotal advance: Hmgb1 expression in active lesions of human and experimental multiple sclerosis. J Leukoc Biol 84(5):1248–1255PubMedGoogle Scholar
  4. Anzai Y, Hayashi M, Fueki N, Kurata K, Ohya T (2006) Protracted juvenile neuronal ceroid lipofuscinosis—an autopsy report and immunohistochemical analysis. Brain Dev 28(7):462–465PubMedGoogle Scholar
  5. Arya R, Lalloz MR, Nicolaides KH, Bellingham AJ, Layton DM (1996) Prenatal diagnosis of triosephosphate isomerase deficiency. Blood 87(11):4507–4509PubMedGoogle Scholar
  6. Berbaum K, Shanmugam K, Stuchbury G, Wiede F, Korner H, Münch G (2008) Induction of novel cytokines and chemokines by advanced glycation endproducts determined with a cytometric bead array. Cytokine 41(3):198–203PubMedGoogle Scholar
  7. Bierhaus A, Haslbeck KM, Humpert PM, Liliensiek B, Dehmer T, Morcos M, Sayed AA, Andrassy M, Schiekofer S, Schneider JG, Schulz JB, Heuss D, Neundorfer B, Dierl S, Huber J, Tritschler H, Schmidt AM, Schwaninger M, Haering HU, Schleicher E, Kasper M, Stern DM, Arnold B, Nawroth PP (2004) Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J Clin Invest 114(12):1741–1751PubMedGoogle Scholar
  8. Bigl K, Gaunitz F, Schmitt A, Rothemund S, Schliebs R, Münch G, Arendt T (2008) Cytotoxicity of advanced glycation endproducts in human micro- and astroglial cell lines depends on the degree of protein glycation. J Neural Transm 115(11):1545–1556PubMedGoogle Scholar
  9. Blatnik M, Frizzell N, Thorpe SR, Baynes JW (2008) Inactivation of glyceraldehyde-3-phosphate dehydrogenase by fumarate in diabetes: Formation of s-(2-succinyl)cysteine, a novel chemical modification of protein and possible biomarker of mitochondrial stress. Diabetes 57(1):41–49PubMedGoogle Scholar
  10. Braak H, Braak E (1988) Neuropil threads occur in dendrites of tangle-bearing nerve cells. Neuropathol Appl Neurobiol 14(1):39–44PubMedGoogle Scholar
  11. Brownlee M (1995) Advanced protein glycosylation in diabetes and aging. Annu Rev Med 46:223–234PubMedGoogle Scholar
  12. Bucht G, Adolfsson R, Lithner F, Winblad B (1983) Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer type. Acta Med Scand 213(5):387–392PubMedGoogle Scholar
  13. Cameron NE, Cotter MA (1993) Potential therapeutic approaches to the treatment or prevention of diabetic neuropathy: evidence from experimental studies. Diabet Med 10(7):593–605PubMedGoogle Scholar
  14. Cameron NE, Cotter MA (2008) Pro-inflammatory mechanisms in diabetic neuropathy: focus on the nuclear factor kappa b pathway. Curr Drug Targets 9(1):60–67PubMedGoogle Scholar
  15. Cameron NE, Eaton SE, Cotter MA, Tesfaye S (2001) Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 44(11):1973–1988PubMedGoogle Scholar
  16. Carini M, Aldini G, Beretta G, Arlandini E, Facino RM (2003) Acrolein-sequestering ability of endogenous dipeptides: characterization of carnosine and homocarnosine/acrolein adducts by electrospray ionization tandem mass spectrometry. J Mass Spectrom 38(9):996–1006PubMedGoogle Scholar
  17. Carubelli R, Schneider JE Jr, Pye QN, Floyd RA (1995) Cytotoxic effects of autoxidative glycation. Free Radic Biol Med 18(2):265–269PubMedGoogle Scholar
  18. Castellani R, Smith MA, Richey PL, Perry G (1996) Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease. Brain Res 737(1–2):195–200PubMedGoogle Scholar
  19. Castellani RJ, Harris PL, Sayre LM, Fujii J, Taniguchi N, Vitek MP, Founds H, Atwood CS, Perry G, Smith MA (2001) Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med 31(2):175–180PubMedGoogle Scholar
  20. Celotto AM, Frank AC, Seigle JL, Palladino MJ (2006) Drosophila model of human inherited triosephosphate isomerase deficiency glycolytic enzymopathy. Genetics 174(3):1237–1246PubMedGoogle Scholar
  21. Chavakis T, Bierhaus A, Al-Fakhri N, Schneider D, Witte S, Linn T, Nagashima M, Morser J, Arnold B, Preissner KT, Nawroth PP (2003) The pattern recognition receptor (rage) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med 198(10):1507–1515PubMedGoogle Scholar
  22. Chou SM, Wang HS, Taniguchi A, Bucala R (1998) Advanced glycation endproducts in neurofilament conglomeration of motoneurons in familial and sporadic amyotrophic lateral sclerosis. Mol Med 4(5):324–332PubMedGoogle Scholar
  23. Cochrane SM, Furth AJ (1993) The role of bound lipid and transition metal in the formation of fluorescent advanced glycation endproducts by human serum albumin. Biochem Soc Trans 21(2):97SPubMedGoogle Scholar
  24. D’Amelio M, Ragonese P, Callari G, Di Benedetto N, Palmeri B, Terruso V, Salemi G, Famoso G, Aridon P, Savettieri G (2009) Diabetes preceding Parkinson’s disease onset. A case–control study. Parkinsonism Relat Disord 15(9):660–664PubMedGoogle Scholar
  25. Dalfo E, Portero-Otin M, Ayala V, Martinez A, Pamplona R, Ferrer I (2005) Evidence of oxidative stress in the neocortex in incidental Lewy body disease. J Neuropathol Exp Neurol 64(9):816–830PubMedGoogle Scholar
  26. Deuther-Conrad W, Loske C, Schinzel R, Dringen R, Riederer P, Münch G (2001) Advanced glycation endproducts change glutathione redox status in sh-sy5y human neuroblastoma cells by a hydrogen peroxide dependent mechanism. Neurosci Lett 312(1):29–32PubMedGoogle Scholar
  27. Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C, Brownlee M (2003) Inhibition of gapdh activity by poly(adp-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest 112(7):1049–1057PubMedGoogle Scholar
  28. Dukic-Stefanovic S, Schinzel R, Riederer P, Münch G (2001) Ages in brain ageing: age-inhibitors as neuroprotective and anti-dementia drugs? Biogerontology 2(1):19–34PubMedGoogle Scholar
  29. Dukic-Stefanovic S, Gasic-Milenkovic J, Deuther-Conrad W, Münch G (2003) Signal transduction pathways in mouse microglia n-11 cells activated by advanced glycation endproducts (ages). J Neurochem 87(1):2609–2615Google Scholar
  30. Duran-Jimenez B, Dobler D, Moffatt S, Rabbani N, Streuli CH, Thornalley PJ, Tomlinson DR, Gardiner NJ (2009) Advanced glycation end products in extracellular matrix proteins contribute to the failure of sensory nerve regeneration in diabetes. Diabetes 58(12):2893–2903PubMedGoogle Scholar
  31. Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, Suffredini AF (2003) Inflammation-promoting activity of hmgb1 on human microvascular endothelial cells. Blood 101(7):2652–2660PubMedGoogle Scholar
  32. Fujisawa Y, Sasaki K, Akiyama K (1991) Increased insulin levels after ogtt load in peripheral blood and cerebrospinal fluid of patients with dementia of Alzheimer type. Biol Psychiatry 30(12):1219–1228PubMedGoogle Scholar
  33. Gasic-Milenkovic J, Loske C, Deuther-Conrad W, Münch G (2001) Protein “ageing”—cytotoxicity of a glycated protein increases with its degree of age-modification. Z Gerontol Geriatr 34(6):457–460PubMedGoogle Scholar
  34. Gasic-Milenkovic J, Dukic-Stefanovic S, Deuther-Conrad W, Gartner U, Münch G (2003) Beta-amyloid peptide potentiates inflammatory responses induced by lipopolysaccharide, interferon-gamma and ‘advanced glycation endproducts’ in a murine microglia cell line. Eur J Neurosci 17(4):813–821PubMedGoogle Scholar
  35. Gasser A, Forbes JM (2008) Advanced glycation: implications in tissue damage and disease. Protein Pept Lett 15(4):385–391PubMedGoogle Scholar
  36. Gerdemann A, Lemke HD, Nothdurft A, Heidland A, Münch G, Bahner U, Schinzel R (2000) Low-molecular but not high-molecular advanced glycation end products (ages) are removed by high-flux dialysis. Clin Nephrol 54(4):276–283PubMedGoogle Scholar
  37. Girones X, Guimera A, Cruz-Sanchez CZ, Ortega A, Sasaki N, Makita Z, Lafuente JV, Kalaria R, Cruz-Sanchez FF (2004) N epsilon-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer’s disease. Free Radic Biol Med 36(10):1241–1247PubMedGoogle Scholar
  38. Gnerer JP, Kreber RA, Ganetzky B (2006) Wasted away, a drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death. Proc Natl Acad Sci USA 103(41):14987–14993PubMedGoogle Scholar
  39. Gotz J (2001) Tau and transgenic animal models. Brain Res Brain Res Rev 35(3):266–286PubMedGoogle Scholar
  40. Gros-Louis F, Gaspar C, Rouleau GA (2006) Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta 1762(11–12):956–972PubMedGoogle Scholar
  41. Hamada K, Kato M, Shimizu T, Ihara K, Mizuno T, Hakoshima T (2005) Crystal structure of the protein histidine phosphatase sixa in the multistep his-asp phosphorelay. Genes Cells 10(1):1–11PubMedGoogle Scholar
  42. Haslbeck KM, Schleicher E, Bierhaus A, Nawroth P, Haslbeck M, Neundorfer B, Heuss D (2005) The age/rage/nf-(kappa)b pathway may contribute to the pathogenesis of polyneuropathy in impaired glucose tolerance (igt). Exp Clin Endocrinol Diabetes 113(5):288–291PubMedGoogle Scholar
  43. Haslbeck KM, Neundorfer B, Schlotzer-Schrehardtt U, Bierhaus A, Schleicher E, Pauli E, Haslbeck M, Hecht M, Nawroth P, Heuss D (2007) Activation of the rage pathway: a general mechanism in the pathogenesis of polyneuropathies? Neurol Res 29(1):103–110PubMedGoogle Scholar
  44. Hipkiss AR (2007) Could carnosine or related structures suppress Alzheimer’s disease? J Alzheimers Dis 11(2):229–240PubMedGoogle Scholar
  45. Horie K, Miyata T, Yasuda T, Takeda A, Yasuda Y, Maeda K, Sobue G, Kurokawa K (1997) Immunohistochemical localization of advanced glycation end products, pentosidine, and carboxymethyllysine in lipofuscin pigments of Alzheimer’s disease and aged neurons. Biochem Biophys Res Commun 236(2):327–332PubMedGoogle Scholar
  46. Hoyer S (1998) Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J Neural Transm 105(4–5):415–422PubMedGoogle Scholar
  47. Hoyer S (2004) Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 490(1–3):115–125PubMedGoogle Scholar
  48. Huijberts MS, Schaper NC, Schalkwijk CG (2008) Advanced glycation end products and diabetic foot disease. Diabetes Metab Res Rev 24(Suppl 1):S19–S24Google Scholar
  49. Ilzecka J (2009) Serum-soluble receptor for advanced glycation end product levels in patients with amyotrophic lateral sclerosis. Acta Neurol Scand 120(2):119–122PubMedGoogle Scholar
  50. Iwata H, Ukeda H, Maruyama T, Fujino T, Sawamura M (2004) Effect of carbonyl compounds on red blood cells deformability. Biochem Biophys Res Commun 321(3):700–706PubMedGoogle Scholar
  51. Jerums G, Panagiotopoulos S, Forbes J, Osicka T, Cooper M (2003) Evolving concepts in advanced glycation, diabetic nephropathy, and diabetic vascular disease. Arch Biochem Biophys 419(1):55–62PubMedGoogle Scholar
  52. Kalousova M, Zima T, Tesar V, Dusilova-Sulkova S, Skrha J (2005) Advanced glycoxidation end products in chronic diseases—clinical chemistry and genetic background. Mutat Res 579(1–2):37–46PubMedGoogle Scholar
  53. Kato S, Takikawa M, Nakashima K, Hirano A, Cleveland DW, Kusaka H, Shibata N, Kato M, Nakano I, Ohama E (2000) New consensus research on neuropathological aspects of familial amyotrophic lateral sclerosis with superoxide dismutase 1 (sod1) gene mutations: inclusions containing sod1 in neurons and astrocytes. Amyotroph Lateral Scler Other Motor Neuron Disord 1(3):163–184PubMedGoogle Scholar
  54. Kikuchi S, Shinpo K, Ogata A, Tsuji S, Takeuchi M, Makita Z, Tashiro K (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(2):63–68PubMedGoogle Scholar
  55. Kikuchi S, Shinpo K, Takeuchi M, Yamagishi S, Makita Z, Sasaki N, Tashiro K (2003) Glycation—a sweet tempter for neuronal death. Brain Res Brain Res Rev 41(2–3):306–323PubMedGoogle Scholar
  56. Kimura T, Takamatsu J, Araki N, Goto M, Kondo A, Miyakawa T, Horiuchi S (1995) Are advanced glycation end-products associated with amyloidosis in Alzheimer’s disease? Neuroreport 6(6):866–868PubMedGoogle Scholar
  57. King RH (2001) The role of glycation in the pathogenesis of diabetic polyneuropathy. Mol Pathol 54(6):400–408PubMedGoogle Scholar
  58. Ko LW, Ko EC, Nacharaju P, Liu WK, Chang E, Kenessey A, Yen SH (1999) An immunochemical study on tau glycation in paired helical filaments. Brain Res 830(2):301–313PubMedGoogle Scholar
  59. Kodl CT, Seaquist ER (2008) Cognitive dysfunction and diabetes mellitus. Endocr Rev 29(4):494–511PubMedGoogle Scholar
  60. Krautwald M, Münch G (2010) Advanced glycation end products as biomarkers and gerontotoxins—a basis to explore methylglyoxal-lowering agents for Alzheimer’s disease? Exp Gerontol 45:744–751PubMedGoogle Scholar
  61. Kuhla B, Loske C, Garcia De Arriba S, Schinzel R, Huber J, Münch G (2004) Differential effects of “advanced glycation endproducts” and beta-amyloid peptide on glucose utilization and atp levels in the neuronal cell line sh-sy5y. J Neural Transm 111(3):427–439PubMedGoogle Scholar
  62. Langemann H, Kabiersch A, Newcombe J (1992) Measurement of low-molecular-weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis. Eur Neurol 32(5):248–252PubMedGoogle Scholar
  63. Ledesma MD, Bonay P, Colaco C, Avila J (1994) Analysis of microtubule-associated protein tau glycation in paired helical filaments. J Biol Chem 269(34):21614–21619PubMedGoogle Scholar
  64. Loske C, Neumann A, Cunningham AM, Nichol K, Schinzel R, Riederer P, Münch G (1998) Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress. J Neural Transm 105(8–9):1005–1015PubMedGoogle Scholar
  65. Loske C, Gerdemann A, Schepl W, Wycislo M, Schinzel R, Palm D, Riederer P, Münch G (2000) Transition metal-mediated glycoxidation accelerates cross-linking of beta-amyloid peptide. Eur J Biochem 267(13):4171–4178PubMedGoogle Scholar
  66. Lukic IK, Humpert PM, Nawroth PP, Bierhaus A (2008) The rage pathway: activation and perpetuation in the pathogenesis of diabetic neuropathy. Ann N Y Acad Sci 1126:76–80PubMedGoogle Scholar
  67. Lüth HJ, Ogunlade V, Kuhla B, Kientsch-Engel R, Stahl P, Webster J, Arendt T, Münch G (2005) Age- and stage-dependent accumulation of advanced glycation end products in intracellular deposits in normal and Alzheimer’s disease brains. Cereb Cortex 15(2):211–220PubMedGoogle Scholar
  68. Miyata S, Liu BF, Shoda H, Ohara T, Yamada H, Suzuki K, Kasuga M (1997) Accumulation of pyrraline-modified albumin in phagocytes due to reduced degradation by lysosomal enzymes. J Biol Chem 272(7):4037–4042PubMedGoogle Scholar
  69. Monnier VM, Cerami A (1981) Nonenzymatic browning in vivo: possible process for aging of long-lived proteins. Science 211(4481):491–493PubMedGoogle Scholar
  70. Mullarkey CJ, Edelstein D, Brownlee M (1990) Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes. Biochem Biophys Res Commun 173(3):932–939PubMedGoogle Scholar
  71. Münch G, Taneli Y, Schraven E, Schindler U, Schinzel R, Palm D, Riederer P (1994) The cognition-enhancing drug tenilsetam is an inhibitor of protein crosslinking by advanced glycosylation. J Neural Transm Park Dis Dement Sect 8(3):193–208PubMedGoogle Scholar
  72. Münch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Muller R, Neumann A, Schinzel R, Cunningham AM (1997a) Influence of advanced glycation end-products and age-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. Biochim Biophys Acta 1360(1):17–29PubMedGoogle Scholar
  73. Münch G, Thome J, Foley P, Schinzel R, Riederer P (1997b) Advanced glycation endproducts in ageing and Alzheimer’s disease. Brain Res Brain Res Rev 23(1–2):134–143PubMedGoogle Scholar
  74. Münch G, Schinzel R, Loske C, Wong A, Durany N, Li JJ, Vlassara H, Smith MA, Perry G, Riederer P (1998) Alzheimer’s disease–synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts. J Neural Transm 105(4–5):439–461PubMedGoogle Scholar
  75. Münch G, Schicktanz D, Behme A, Gerlach M, Riederer P, Palm D, Schinzel R (1999) Amino acid specificity of glycation and protein-age crosslinking reactivities determined with a dipeptide spot library. Nat Biotechnol 17(10):1006–1010PubMedGoogle Scholar
  76. Münch G, Lüth HJ, Wong A, Arendt T, Hirsch E, Ravid R, Riederer P (2000) Crosslinking of alpha-synuclein by advanced glycation endproducts—an early pathophysiological step in Lewy body formation? J Chem Neuroanat 20(3–4):253–257PubMedGoogle Scholar
  77. Muscat S, Pelka J, Hegele J, Weigle B, Münch G, Pischetsrieder M (2007) Coffee and maillard products activate nf-kappab in macrophages via h(2)o(2) production. Mol Nutr Food Res 51:525–535PubMedGoogle Scholar
  78. Obrosova IG (2002) How does glucose generate oxidative stress in peripheral nerve? Int Rev Neurobiol 50:3–35PubMedGoogle Scholar
  79. Obrosova IG (2003) Update on the pathogenesis of diabetic neuropathy. Curr Diab Rep 3(6):439–445PubMedGoogle Scholar
  80. Obrosova IG (2009) Diabetes and the peripheral nerve. Biochim Biophys Acta 1792(10):931–940PubMedGoogle Scholar
  81. Obrosova IG, Li F, Abatan OI, Forsell MA, Komjati K, Pacher P, Szabo C, Stevens MJ (2004) Role of poly(adp-ribose) polymerase activation in diabetic neuropathy. Diabetes 53(3):711–720PubMedGoogle Scholar
  82. Olah J, Orosz F, Keseru GM, Kovari Z, Kovacs J, Hollan S, Ovadi J (2002) Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease. Biochem Soc Trans 30(2):30–38PubMedGoogle Scholar
  83. Orosz F, Olah J, Alvarez M, Keseru GM, Szabo B, Wagner G, Kovari Z, Horanyi M, Baroti K, Martial JA, Hollan S, Ovadi J (2001) Distinct behavior of mutant triosephosphate isomerase in hemolysate and in isolated form: molecular basis of enzyme deficiency. Blood 98(10):3106–3112PubMedGoogle Scholar
  84. Ortwerth BJ, James H, Simpson G, Linetsky M (1998) The generation of superoxide anions in glycation reactions with sugars, osones, and 3-deoxyosones. Biochem Biophys Res Commun 245(1):161–165PubMedGoogle Scholar
  85. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM (1999) Diabetes mellitus and the risk of dementia: the rotterdam study. Neurology 53(9):1937–1942PubMedGoogle Scholar
  86. Pacher P, Obrosova IG, Mabley JG, Szabo C (2005) Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. Curr Med Chem 12(3):267–275PubMedGoogle Scholar
  87. Pasinelli P, Brown RH (2006) Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci 7(9):710–723PubMedGoogle Scholar
  88. Peppa M, Stavroulakis P, Raptis SA (2009) Advanced glycoxidation products and impaired diabetic wound healing. Wound Repair Regen 17(4):461–472PubMedGoogle Scholar
  89. Rabbani N, Thornalley PJ (2008) Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress. Biochem Soc Trans 36(Pt 5):1045–1050PubMedGoogle Scholar
  90. Rabbani N, Alam SS, Riaz S, Larkin JR, Akhtar MW, Shafi T, Thornalley PJ (2009) High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia 52(2):208–212PubMedGoogle Scholar
  91. Reddy VP, Garrett MR, Perry G, Smith MA (2005) Carnosine: a versatile antioxidant and antiglycating agent. Sci Aging Knowledge Environ 18:pe12Google Scholar
  92. Rong LL, Yan SF, Wendt T, Hans D, Pachydaki S, Bucciarelli LG, Adebayo A, Qu W, Lu Y, Kostov K, Lalla E, Yan SD, Gooch C, Szabolcs M, Trojaborg W, Hays AP, Schmidt AM (2004) Rage modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways. FASEB J 18(15):1818–1825PubMedGoogle Scholar
  93. Rong LL, Gooch C, Szabolcs M, Herold KC, Lalla E, Hays AP, Yan SF, Yan SS, Schmidt AM (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(5–6):355–365PubMedGoogle Scholar
  94. Said G (2007) Diabetic neuropathy—a review. Nat Clin Pract Neurol 3(6):331–340PubMedGoogle Scholar
  95. Sakaguchi T, Yan SF, Yan SD, Belov D, Rong LL, Sousa M, Andrassy M, Marso SP, Duda S, Arnold B, Liliensiek B, Nawroth PP, Stern DM, Schmidt AM, Naka Y (2003) Central role of rage-dependent neointimal expansion in arterial restenosis. J Clin Invest 111(7):959–972PubMedGoogle Scholar
  96. Salkovic-Petrisic M, Hoyer S (2007) Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl 72:217–233PubMedGoogle Scholar
  97. Sasaki N, Fukatsu R, Tsuzuki K, Hayashi Y, Yoshida T, Fujii N, Koike T, Wakayama I, Yanagihara R, Garruto R, Amano N, Makita Z (1998) Advanced glycation end products in Alzheimer’s disease and other neurodegenerative diseases. Am J Pathol 153(4):1149–1155PubMedGoogle Scholar
  98. Sasaki N, Takeuchi M, Chowei H, Kikuchi S, Hayashi Y, Nakano N, Ikeda H, Yamagishi S, Kitamoto T, Saito T, Makita Z (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(2):117–120PubMedGoogle Scholar
  99. Schneider AS (2000) Triosephosphate isomerase deficiency: historical perspectives and molecular aspects. Baillieres Best Pract Res Clin Haematol 13(1):119–140PubMedGoogle Scholar
  100. Sebekova K, Schinzel R, Ling Simm HA, Xiang G, Gekle M, Münch G, Vamvakas S, Heidland A (1998) Advanced glycated albumin impairs protein degradation in the kidney proximal tubules cell line llc-pk1. Cell Mol Biol (Noisy-le-grand) 44(7):1051–1060Google Scholar
  101. Shibata N, Hirano A, Kato S, Nagai R, Horiuchi S, Komori T, Umahara T, Asayama K, Kobayashi M (1999) Advanced glycation endproducts are deposited in neuronal hyaline inclusions: a study on familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation. Acta Neuropathol (Berl) 97(3):240–246Google Scholar
  102. Shibata N, Hirano A, Hedley-Whyte ET, Dal Canto MC, Nagai R, Uchida K, Horiuchi S, Kawaguchi M, Yamamoto T, Kobayashi M (2002a) Selective formation of certain advanced glycation end products in spinal cord astrocytes of humans and mice with superoxide dismutase-1 mutation. Acta Neuropathol (Berl) 104(2):171–178Google Scholar
  103. Shibata N, Oda H, Hirano A, Kato Y, Kawaguchi M, Dal Canto MC, Uchida K, Sawada T, Kobayashi M (2002b) Molecular biological approaches to neurological disorders including knockout and transgenic mouse models. Neuropathology 22(4):337–349PubMedGoogle Scholar
  104. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD (1994) Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 36(3):348–355PubMedGoogle Scholar
  105. Smith MA, Perry G (1994) Alzheimer disease: an imbalance of proteolytic regulation? Med Hypotheses 42(4):277–279PubMedGoogle Scholar
  106. Smith MA, Taneda S, Richey PL, Miyata S, Yan SD, Stern D, Sayre LM, Monnier VM, Perry G (1994) Advanced maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl Acad Sci USA 91(12):5710–5714PubMedGoogle Scholar
  107. Smith MA, Monnier VM, Sayre LM, Perry G (1995) Amyloidosis, advanced glycation end products and Alzheimer disease. Neuroreport 6(12):1595–1596PubMedGoogle Scholar
  108. Smith MA, Sayre LM, Perry G (1996a) Diabetes mellitus and Alzheimer’s disease: glycation as a biochemical link. Diabetologia 39(2):247PubMedGoogle Scholar
  109. Smith MA, Tabaton M, Perry G (1996b) Early contribution of oxidative glycation in Alzheimer disease. Neurosci Lett 217(2–3):210–211PubMedGoogle Scholar
  110. Southern L, Williams J, Esiri MM (2007) Immunohistochemical study of n-epsilon-carboxymethyl lysine (cml) in human brain: relation to vascular dementia. BMC Neurol 7:35PubMedGoogle Scholar
  111. Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, Münch G (2009) Advanced glycation endproducts and their receptor rage in Alzheimer’s disease. Neurobiol Aging 247:809–814Google Scholar
  112. Sternberg Z, Weinstock-Guttman B, Hojnacki D, Zamboni P, Zivadinov R, Chadha K, Lieberman A, Kazim L, Drake A, Rocco P, Grazioli E, Munschauer F (2008) Soluble receptor for advanced glycation end products in multiple sclerosis: a potential marker of disease severity. Mult Scler 14(6):759–763PubMedGoogle Scholar
  113. Stolzing A, Widmer R, Jung T, Voss P, Grune T (2006) Degradation of glycated bovine serum albumin in microglial cells. Free Radic Biol Med 40(6):1017–1027PubMedGoogle Scholar
  114. Sugimoto K, Yasujima M, Yagihashi S (2008) Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des 14(10):953–961PubMedGoogle Scholar
  115. Takamiya R, Takahashi M, Myint T, Park YS, Miyazawa N, Endo T, Fujiwara N, Sakiyama H, Misonou Y, Miyamoto Y, Fujii J, Taniguchi N (2003) Glycation proceeds faster in mutated cu, zn-superoxide dismutases related to familial amyotrophic lateral sclerosis. FASEB J 17(8):938–940PubMedGoogle Scholar
  116. Takedo A, Yasuda T, Miyata T, Mizuno K, Li M, Yoneyama S, Horie K, Maeda K, Sobue G (1996) Immunohistochemical study of advanced glycation end products in aging and Alzheimer’s disease brain. Neurosci Lett 221(1):17–20PubMedGoogle Scholar
  117. Thome J, Kornhuber J, Münch G, Schinzel R, Taneli Y, Zielke B, Rosler M, Riederer P (1996) [new hypothesis on etiopathogenesis of Alzheimer syndrome. Advanced glycation end products (ages)]. Nervenarzt 67(11):924–929PubMedGoogle Scholar
  118. Thornalley PJ (1988) Modification of the glyoxalase system in human red blood cells by glucose in vitro. Biochem J 254(3):751–755PubMedGoogle Scholar
  119. Thornalley PJ (2002) Glycation in diabetic neuropathy: characteristics, consequences, causes, and therapeutic options. Int Rev Neurobiol 50:37–57PubMedGoogle Scholar
  120. Thornalley PJ (2005) The potential role of thiamine (vitamin b1) in diabetic complications. Curr Diabetes Rev 1(3):287–298PubMedGoogle Scholar
  121. Thorpe SR, Baynes JW (1996) Role of the maillard reaction in diabetes mellitus and diseases of aging. Drugs Aging 9(2):69–77PubMedGoogle Scholar
  122. Toth C, Martinez J, Zochodne DW (2007a) Rage, diabetes, and the nervous system. Curr Mol Med 7(8):766–776PubMedGoogle Scholar
  123. Toth C, Rong LL, Yang C, Martinez J, Song F, Ramji N, Brussee V, Liu W, Durand J, Nguyen MD, Schmidt AM, Zochodne DW (2007b) Rage and experimental diabetic neuropathy. Diabetes 57:1002–1017PubMedGoogle Scholar
  124. Toth C, Rong LL, Yang C, Martinez J, Song F, Ramji N, Brussee V, Liu W, Durand J, Nguyen MD, Schmidt AM, Zochodne DW (2008) Receptor for advanced glycation end products (rages) and experimental diabetic neuropathy. Diabetes 57(4):1002–1017PubMedGoogle Scholar
  125. Vallianou N, Evangelopoulos A, Koutalas P (2009) Alpha-lipoic acid and diabetic neuropathy. Rev Diabet Stud 6(4):230–236PubMedGoogle Scholar
  126. Vicente Miranda H, Outeiro TF (2010) The sour side of neurodegenerative disorders: the effects of protein glycation. J Pathol 221(1):13–25PubMedGoogle Scholar
  127. Vincent AM, Perrone L, Sullivan KA, Backus C, Sastry AM, Lastoskie C, Feldman EL (2007) Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress. Endocrinology 148(2):548–558PubMedGoogle Scholar
  128. Vinik A, Ullal J, Parson HK, Casellini CM (2006) Diabetic neuropathies: clinical manifestations and current treatment options. Nat Clin Pract Endocrinol Metab 2(5):269–281PubMedGoogle Scholar
  129. Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, Manogue K, Cerami A (1994) Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci USA 91(11):4766–4770PubMedGoogle Scholar
  130. Webster J, Urban C, Berbaum K, Loske C, Alpar A, Gartner U, de Arriba SG, Arendt T, Münch G (2005) The carbonyl scavengers aminoguanidine and tenilsetam protect against the neurotoxic effects of methylglyoxal. Neurotox Res 7(1–2):95–101PubMedGoogle Scholar
  131. Wilmshurst JM, Wise GA, Pollard JD, Ouvrier RA (2004) Chronic axonal neuropathy with triosephosphate isomerase deficiency. Pediatr Neurol 30(2):146–148PubMedGoogle Scholar
  132. Wolff SP, Bascal ZA, Hunt JV (1989) “Autoxidative glycosylation”: free radicals and glycation theory. Prog Clin Biol Res 304:259–275PubMedGoogle Scholar
  133. Wong A, Lüth HJ, Deuther-Conrad W, Dukic-Stefanovic S, Gasic-Milenkovic J, Arendt T, Münch G (2001) Advanced glycation endproducts co-localize with inducible nitric oxide synthase in Alzheimer’s disease. Brain Res 920(1–2):32–40PubMedGoogle Scholar
  134. Wu S, Ren J (2006) Benfotiamine alleviates diabetes-induced cerebral oxidative damage independent of advanced glycation end-product, tissue factor and tnf-alpha. Neurosci Lett 394(2):158–162PubMedGoogle Scholar
  135. Yagihashi S, Yamagishi S, Wada R (2007) Pathology and pathogenetic mechanisms of diabetic neuropathy: correlation with clinical signs and symptoms. Diabetes Res Clin Pract 77(Suppl 1):S184–S189PubMedGoogle Scholar
  136. Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, Scott CW, Caputo C, Frappier T, Smith MA et al (1994) Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci USA 91(16):7787–7791PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Gerald Münch
    • 1
    • 3
  • Bernadette Westcott
    • 1
  • Teresita Menini
    • 2
  • Alejandro Gugliucci
    • 2
  1. 1.Molecular Medicine Research Group, Department of Pharmacology, School of MedicineUniversity of Western SydneyCampbelltownAustralia
  2. 2.Glycation, Oxidation and Disease LaboratoryTouro University-CaliforniaVallejoUSA
  3. 3.Department of Pharmacology, School of MedicineUniversity of Western SydneyPenrith South DCAustralia

Personalised recommendations