AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs?

In Alzheimer's disease, age-related cellular changes such ascompromised energy production and increased radical formation areworsened by the presence of AGEs as additional, AD specificstress factors. Intracellular AGEs (most likely derived frommethylglyoxal) crosslink cytoskeletal proteins and render theminsoluble. These aggregates inhibit cellular functions includingtransport processes and contribute to neuronal dysfunction anddeath. Extracellular AGEs, which accumulate in ageing tissue (butmost prominently on long-lived protein deposits like the senileplaques) exert chronic oxidative stress on neurons. In addition,they activate glial cells to produce free radicals (superoxideand NO) and neurotoxic cytokines such as TNF-α. Drugs, whichinhibit the formation of AGEs by specific chemical mechanisms(AGE-inhibitors), including aminoguanidine, carnosine,tenilsetam, OPB-9195 and pyridoxamine, attenuate the developmentof (AGE-mediated) diabetic complications. Assuming that `carbonylstress' contributes significantly to the progression ofAlzheimer's disease, AGE-inhibitors might also becomeinteresting novel therapeutic drugs for treatment of AD.

[1]  P. Riederer,et al.  Transition metal-mediated glycoxidation accelerates cross-linking of beta-amyloid peptide. , 2000, European journal of biochemistry.

[2]  P. Riederer,et al.  Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress , 1998, Journal of Neural Transmission.

[3]  J. Baynes,et al.  Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose. , 1995, Biochemistry.

[4]  M. Jadoul,et al.  Accumulation of carbonyls accelerates the formation of pentosidine, an advanced glycation end product: carbonyl stress in uremia. , 1998, Journal of the American Society of Nephrology : JASN.

[5]  T. Luther,et al.  Advanced Glycation End Product-Induced Activation of NF-κB is Suppressed by α-Lipoic Acid in Cultured Endothelial Cells , 1997, Diabetes.

[6]  J. Ávila,et al.  Analysis of microtubule-associated protein tau glycation in paired helical filaments. , 1994, The Journal of biological chemistry.

[7]  W. Griffin,et al.  Microglial inter leukin‐1α expression in brain regions in Alzheimer's disease: correlation with neuritic plaque distribution , 1995, Neuropathology and applied neurobiology.

[8]  Paul J Thornalley,et al.  Rapid hydrolysis and slow α,β-dicarbonyl cleavage of an agent proposed to cleave glucose-derived protein cross-links , 1999 .

[9]  A. Jenkins,et al.  Pyridoxamine, an Inhibitor of Advanced Glycation Reactions, Also Inhibits Advanced Lipoxidation Reactions , 2000, The Journal of Biological Chemistry.

[10]  A. Heidland,et al.  Advanced glycation endproducts stimulate the MAP‐kinase pathway in tubulus cell line LLC‐PK1 , 1997, FEBS letters.

[11]  R. Schliebs,et al.  Induction of cytokines in glial cells surrounding cortical β-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology , 2000, International Journal of Developmental Neuroscience.

[12]  Paul J Thornalley,et al.  Synthesis and secretion of macrophage colony stimulating factor by mature human monocytes and human monocytic THP-1 cells induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. , 1996, Immunology letters.

[13]  R. Ihl,et al.  Effects of 3 months treatment with tenilsetam in patients suffering from dementia of Alzheimer type (DAT) , 1989 .

[14]  A. Bush,et al.  Metals and neuroscience. , 2000, Current opinion in chemical biology.

[15]  P. Syrris,et al.  Non‐enzymatic glycosylation of the dipeptide l‐carnosine, a potential anti‐protein‐cross‐linking agent , 1995, FEBS letters.

[16]  A. Roher,et al.  RAGE-AB Interactions in the Pathophysiology of Alzheimer's Disease , 1998 .

[17]  G. Perry,et al.  Advanced Maillard reaction end products are associated with Alzheimer disease pathology. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Paul J Thornalley,et al.  Accumulation of α-oxoaldehydes during oxidative stress: a role in cytotoxicity , 1999 .

[19]  M. Smith,et al.  Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. , 1997, The American journal of pathology.

[20]  Z. Makita,et al.  Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. , 1998, The American journal of pathology.

[21]  E. Mandelkow,et al.  On the structure of microtubules, tau, and paired helical filaments , 1995, Neurobiology of Aging.

[22]  B. Vanhaesebroeck,et al.  A Redox-triggered Ras-Effector Interaction , 1998, The Journal of Biological Chemistry.

[23]  A. Hipkiss,et al.  Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine. , 1998, Neuroscience letters.

[24]  H. Yamamoto,et al.  Advanced glycation endproducts-receptor interactions stimulate the growth of human pancreatic cancer cells through the induction of platelet-derived growth factor-B. , 1996, Biochemical and biophysical research communications.

[25]  G. Sobue,et al.  Advanced glycation end products co-localized with astrocytes and microglial cells in Alzheimer’s disease brain , 1998, Acta Neuropathologica.

[26]  H. Tritschler,et al.  Alpha-lipoic acid reduces expression of vascular cell adhesion molecule-1 and endothelial adhesion of human monocytes after stimulation with advanced glycation end products. , 1999, Clinical science.

[27]  G. Sobue,et al.  Immunohistochemical localization of advanced glycation end products, pentosidine, and carboxymethyllysine in lipofuscin pigments of Alzheimer's disease and aged neurons. , 1997, Biochemical and biophysical research communications.

[28]  D. Dickson,et al.  Glycation and microglial reaction in lesions of Alzheimer's disease , 1996, Neurobiology of Aging.

[29]  K. Tracey,et al.  Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Ávila,et al.  Tau glycation is involved in aggregation of the protein but not in the formation of filaments. , 1998, Cellular and molecular biology.

[31]  T. Miyata,et al.  Localization of identified advanced glycation end‐product structures, Nε=(carboxymethyl)lysine and pentosidine, in age‐related inclusions in human brains , 1998, Pathology international.

[32]  Yong Ming Li,et al.  Enhanced binding of advanced glycation endproducts (AGE) by the ApoE4 isoform links the mechanism of plaque deposition in Alzheimer's disease , 1997, Neuroscience Letters.

[33]  G. Sobue,et al.  Immunohistochemical study of advanced glycation end products in aging and Alzheimer's disease brain , 1996, Neuroscience Letters.

[34]  M. Smith,et al.  Amyloidosis, advanced glycation end products and Alzheimer disease. , 1995, Neuroreport.

[35]  J. Zweier,et al.  Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide , 1995, Nature Medicine.

[36]  L. Mucke,et al.  Cellular signaling roles of TGF beta, TNF alpha and beta APP in brain injury responses and Alzheimer's disease. , 1997, Brain research. Brain research reviews.

[37]  D. Choudhury,et al.  Advanced glycation end products: a Nephrologist's perspective. , 2000, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[38]  P. Riederer,et al.  High molecular weight hyaluronic acid inhibits advanced glycation endproduct‐induced NF‐κB activation and cytokine expression , 1999 .

[39]  H. Makino,et al.  Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-α and inducible nitric oxide synthase in diabetic rat glomeruli , 1999, Diabetologia.

[40]  E. Braak,et al.  Advanced glycation endproducts are associated with Hirano bodies in Alzheimer's disease , 1998, Brain Research.

[41]  Z. Makita,et al.  Progression of Nephropathy in Spontaneous Diabetic Rats Is Prevented by OPB-9195, a Novel Inhibitor of Advanced Glycation , 1997, Diabetes.

[42]  A. Raina,et al.  The role of cell cycle‐mediated events in Alzheimer's disease , 1999, International journal of experimental pathology.

[43]  Paul L. Wood,et al.  Cytokine indices in Alzheimer's temporal cortex: no changes in mature IL-1β or IL-1RA but increases in the associated acute phase proteins IL-6, α2-macroglobulin and C-reactive protein , 1993, Brain Research.

[44]  A. Booth,et al.  Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation end-products: comparison with aminoguanidine. , 1996, Biochemical and biophysical research communications.

[45]  A. Roher,et al.  RAGE-Abeta interactions in the pathophysiology of Alzheimer's disease. , 1998, Restorative neurology and neuroscience.

[46]  H. Tritschler,et al.  α-Lipoic acid reduces expression of vascular cell adhesion molecule-1 and endothelial adhesion of human monocytes after stimulation with advanced glycation end products , 1999 .

[47]  M. Smith,et al.  Is increased redox-active iron in Alzheimer disease a failure of the copper-binding protein ceruloplasmin? , 1999, Free radical biology & medicine.

[48]  Paul J Thornalley,et al.  Rapid hydrolysis and slow alpha,beta-dicarbonyl cleavage of an agent proposed to cleave glucose-derived protein cross-links. , 1999, Biochemical pharmacology.

[49]  J. Ávila,et al.  The role of the Maillard reaction in other pathologies: Alzheimer's disease. , 1996, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[50]  A. Hipkiss,et al.  Toxic effects of β-amyloid(25–35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and β-alanine , 1998, Neuroscience Letters.

[51]  Y. Kaneda,et al.  Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage , 2000, Nature.

[52]  Paul J Thornalley,et al.  Accumulation of alpha-oxoaldehydes during oxidative stress: a role in cytotoxicity. , 1999, Biochemical pharmacology.

[53]  L. Mucke,et al.  Cellular signaling roles of TGFβ, TNFα and βAPP in brain injury responses and Alzheimer's disease , 1997, Brain Research Reviews.

[54]  G. Romeo,et al.  Upregulation of Mesangial Growth Factor and Extracellular Matrix Synthesis by Advanced Glycation End Products Via a Receptor-Mediated Mechanism , 1997, Diabetes.

[55]  R. Heumann,et al.  Induction of p21ras in Alzheimer pathology. , 1995, Neuroreport.

[56]  R. Bucala,et al.  Advanced glycation end products contribute to amyloidosis in Alzheimer disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[57]  U. Gärtner,et al.  Expression of the cyclin‐dependent kinase inhibitor p16 in Alzheimer's disease , 1996, Neuroreport.

[58]  Wei Liu,et al.  Carbonyl compounds cross‐link cellular proteins and activate protein‐tyrosine kinase p60c‐Src , 1999, Journal of cellular biochemistry.

[59]  C. Heizmann,et al.  S100 proteins in Corpora Amylacea from normal human brain 1 1 Published on the World Wide Web on 5 May 2000. , 2000, Brain Research.

[60]  C. Fitzgerald,et al.  Carnosine prevents glyceraldehyde 3-phosphate-mediated inhibition of aspartate aminotransferase , 1999, Archives of Toxicology.

[61]  N. Nakamura,et al.  Advanced glycation end products induce expression of vascular endothelial growth factor by retinal Muller cells. , 1997, Biochemical and biophysical research communications.

[62]  M. Brownlee,et al.  Advanced protein glycosylation in diabetes and aging. , 1995, Annual review of medicine.

[63]  W. Hung,et al.  Role of the Janus kinase (JAK)/signal transducters and activators of transcription (STAT) cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells. , 1999, The Biochemical journal.

[64]  A. Hipkiss,et al.  Carnosine reacts with a glycated protein. , 2000, Free radical biology & medicine.

[65]  K. Tatsumi,et al.  2‐Isopropylidenehydrazono‐4‐oxo‐thiazolidin‐5‐ylacetanilide (OPB‐9195) treatment inhibits the development of intimal thickening after balloon injury of rat carotid artery: role of glycoxidation and lipoxidation reactions in vascular tissue damage , 1999, FEBS letters.

[66]  Paul J Thornalley,et al.  Synthesis and secretion of tumour necrosis factor-alpha by human monocytic THP-1 cells and chemotaxis induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. , 1997, Immunology letters.

[67]  P. Riederer,et al.  The cognition-enhancing drug tenilsetam is an inhibitor of protein crosslinking by advanced glycosylation , 1994, Journal of neural transmission. Parkinson's disease and dementia section.

[68]  T. Miyata,et al.  Neurotoxicity of methylglyoxal and 3‐deoxyglucosone on cultured cortical neurons: Synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases , 1999, Journal of neuroscience research.

[69]  S. Yen,et al.  An immunochemical study on tau glycation in paired helical filaments , 1999, Brain Research.

[70]  J. Ávila,et al.  τ Protein from Alzheimer's Disease Patients Is Glycated at Its Tubulin‐Binding Domain , 1995, Journal of neurochemistry.

[71]  C. Bouras,et al.  Age-dependent accumulation of advanced glycosylation end products in human neurons , 1995, Neurobiology of Aging.

[72]  T. Brown,et al.  Fructose-3-phosphate production and polyol pathway metabolism in diabetic rat hearts. , 1997, Metabolism: clinical and experimental.

[73]  Paul J Thornalley,et al.  Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. , 1998, The Journal of clinical investigation.

[74]  T. Luther,et al.  Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. , 1997, Diabetes.

[75]  M. Kasuga,et al.  Inhibitory effects of tenilsetam on the Maillard reaction. , 1997, Endocrinology.

[76]  A. Hipkiss.  Carnosine, a protective, anti-ageing peptide? , 1998, The international journal of biochemistry & cell biology.

[77]  P. Riederer,et al.  Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. , 1997, Biochimica et biophysica acta.

[78]  W. G. Mclean,et al.  The Role of the Axonal Cytoskeleton in Diabetic Neuropathy , 1997, Neurochemical Research.

[79]  João Nicanildo Bastos dos Santos.  Movement of the rhabditiform larva of Strongyloides stercoralis , 1993, The Lancet.

[80]  G. Striker,et al.  Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[81]  T. Holak,et al.  Model Studies of the Maillard Reaction of Arg-Lys with D-Glucose , 1999 .

[82]  T. Kishimoto,et al.  Advanced Glycation Endproducts Stimulate Interleukin‐6 Production by Human Bone‐Derived Cells , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[83]  M. Smith,et al.  Redox metals and neurodegenerative disease. , 1999, Current opinion in chemical biology.

[84]  Paul J Thornalley,et al.  The reaction of methylglyoxal with aminoguanidine under physiological conditions and prevention of methylglyoxal binding to plasma proteins. , 1994, Biochemical pharmacology.

[85]  A. Schmidt,et al.  Activation of the Receptor for Advanced Glycation End Products Triggers a p21 ras -dependent Mitogen-activated Protein Kinase Pathway Regulated by Oxidant Stress* , 1997, The Journal of Biological Chemistry.

[86]  J. Eaton,et al.  Transition metals bind to glycated proteins forming redox active "glycochelates": implications for the pathogenesis of certain diabetic complications. , 1998, Biochemical and biophysical research communications.

[87]  Z. Makita,et al.  Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195 , 1999, Diabetologia.

[88]  R. Khalifah,et al.  Amadorins: novel post-Amadori inhibitors of advanced glycation reactions. , 1999, Biochemical and biophysical research communications.

[89]  J Bohl,et al.  Staging of Alzheimer-Related Cortical Destruction , 1997, International Psychogeriatrics.