the amino groups of proteins , particularly the side chain of lysine , arginine , and histidine react non - enzymatically with reducing sugars . this post - translational modification called  glycation  or , leads via reversible schiff - base adducts to protein bound amadori products . by subsequent oxidation and dehydration , a broad range of brown heterogeneous products , mostly fluorescent with nitrogen- and oxygen- containing heterocyclic compounds , called advanced glycation end products ( ages ) are formed . the formation of aegs is irreversible , and causes a resistant protein deposition to protease . maillard a chemist , who reported the formation of brown products upon heating a solution of amino acid ( aa ) and sugar . schematic representation of the maillard reaction ( a ) and structures of ages ( b , c and d ) , are shown in figure 1 . pathological consequences of ages 
  in vivo glycation modifies the structural properties of proteins such as albumin and haemoglobin leading to inflammation and oxidative stress . the pathological role of ages in diseases such as diabetes mellitus ( dm ) is not fully understood . in addition to change of the protein structure , the receptor mediated mechanism of ages is of special interest . schematic representation of the maillard reaction ( a ) and structure of advanced glycation end products ages ( b , c and d ) . the pathological features of ages , which are not receptor mediated , can be observed in the progression of cataracts . evidence suggests that the glycation of lens protein is one of the causes of cataract , and is observed in long - lived proteins such as collagen and eye crystalline . however , the pivotal role of ages and the interaction with the receptor is not fully understood . advanced glycation end products and ageing 
  ageing can be characterized as progressive impairment of organs , tissue and cells . it is a progressive process , and not categorized as a disease , unless it interferes with the normal function of the organs . diabetes mellitus and alzheimer s disease ( ad ) are the most prevalent ageing diseases , and are examples of the tissue impairment by ageing . one of the characteristics of ageing is the acceleration of production of glycated proteins and accumulation of them in different tissues . glycated proteins form aggregations , which are insoluble and resistant to degradation in comparison to non - glycated proteins . 
 advanced glycation end products and 
 alzheimer s disease 
  alzheimer s disease is the most common type of dementia in elderly people . approximately four million people in the united states have ad , and this number is expected to increase by 2050 . the prevalence of ad amongst people aged 85 years or older is estimated to increase seven - fold from 1980 to 2050 , however , this rise is slower in people from the age of 65 - 74 years during the period of 1980 to 2050 . alzheimer s disease is characterized by initial mild memory impairment , and progresses to the loss of mental and physical activities . the cognitive decline is associated with widespread loss of synapses , neuronal cell death and the formation of amyloid plaques and neurofibrillary tangles , markers of ad . advanced glycation end products modification and resulting cross - linking of protein deposits were observed to occur in both plaques and tangles . advanced glycation end products receptor 
  for the first time in 1992 , macrophages were described to uptake ages via a specific receptor called advanced glycation end products receptor ( rage ) . the receptor has been identified in monocytes , macrophages , microglia , astrocytes , neurons as well as smooth muscle and endothelial cells . different age modified proteins such as ages and -sheet fibrils like amyloid proteins and other ligand families such as high - mobility - group b and s100/calgranulin were identified as ligands of rage . the interaction between rage and ages is a complicated process , which has been shown to be a cause of problems in different ageing related diseases . increased expression levels of rage were found in the optic nerve of ad patients in proximity to astrocytes . while there are many studies regarding ages , there is not much information about the receptors . the current data show that glycated modified protein binding to rage triggers some components of different signalling pathways . the rage and mitogen - activated protein kinases 
  the rage is a 35 kda age - binding protein belong to the immunoglobulin ( ig ) superfamily . the mitogen activated protein kinases such as extracellular signal - regulated kinase and c - jun n - terminal kinase were implicated to be components of the rage signalling pathways . these mapks are induced by cytokines and stressors . further down in the signal transduction cascade , transcription factors like nuclear factor - kappab are also activated . the cascade of signal transduction depends on the binding of ages to rage , as blocking rage with either an excess of srage or anti - rage antibody prevents cellular activation . it contains an extracellular part with 320 aa , a single transmembrane domain with 21 aa and a short cytoplasmic domain with 40 aa . the extracellular part is composed of a variable domain and two constant ( c ) domains . it has 94 aa in ig - like v - type domain , 98 aa in ig - like c2-type 1 domain and 91 aa in ig - like c2-type 2 domain . alternative splicing plays a major role in the production of different rage isoforms . during alternative rna splicing , exons or introns generally there are four main rage isoforms : full length -rage , n - terminal truncated -rage , endogenous secretary ( es)-rage , and soluble ( s)-rage ( figure 2 ) . soluble - rage and es - rage have similar patterns ; however , s - rage may have some differences compared with es - rage in some aa . soluble - rage is also a product of recombinant technology as well as the cleavage of cell surface rage by extracellular metalloproteinases . soluble - rage and es - rage do not have the cytoplasmic and transmembrane domains of fl - rage . this intron includes a stop codon in the sequence . because of this stop codon , this sequence encodes the transmembrane domain of fl - rage ; therefore , s - rage lacks the transmembrane and cytoplasmic domain . it can not act as a fl - rage and different ligands can not bind to nt - rage . the ligands of rage such as amphoterin , s100b and a oligomer bind to v domain , however , some ligands such as a also bind to c domain . moreover , there are two n - glycosylation sites in and close to the age binding domain . osawa et al , showed that a g82s mutation in the second n - glycosylation motif increased the ages affinity in cos-7 cells . as the blood levels of sugar is high in diabetic patients , translational modification of rage by de n - glycosylation and n - glycosylation sites could be a potential reason for rage activation and deactivation . different splice variants of advanced glycation end products receptor ( rage ) in human brain : fl ( full length rage)-rage , nt ( n - terminal truncated)-rage , es ( endogenous secretary)-rage and s ( soluble)-rage . in addition , s - rage can suppress the rage signalling , and the administration of s - rage was shown to suppresses tumor growth and autoimmune response in animal models for cancer and multiple sclerosis suppresses . the s - rage plasma level is lower in patients with cognitive impairment , non - alcoholic fatty liver disease or type 2 diabetic in comparison with the control . soluble - rage : a marker and a treatment 
  soluble - rage is the extracellular ligand binding domain of rage . it flows in the human plasma and has the potential to function as a decoy for rage signalling pathway by binding to circularising plasma ages . it has been suggested that s - rage can be a biomarker for rage - mediated disease development , especially vascular diseases . there are controversial studies regarding the s - rage plasma level and its relationship to the development of diseases . some studies showed low s - rage plasma level and high n - carboxymethyllysine levels , and abundant natural ages in diabetic patients with severe complications . on the other hand , the s - rage plasma levels are lower in patients with arthritis and hypertension in comparison with healthy patients . yamagishi et al , reported a positive relationship between plasma level of ages and s - rage in non - diabetic population . interestingly , one study reported the elevated plasma levels of s - rage in septic patients . the study was the only to report high s - rage plasma levels in acute and non - chronic diseases . it was proposed that the s - rage plasma level was negatively correlated with body mass index , as overweight people with higher bmi had a lower s - rage plasma level . remarkably , higher s - rage positively correlates with an increase in inflammatory markers such as tumor necrosis factor - and monocyte chemo attractant protein-1 in patients with type-2 diabetes . the decoy characteristic of s - rage is not completely known to function as a negative feedback , as a biomarker , or as a protective factor , which acts by increasing the ages level in plasma in different diseases . recombinant s - rage administration was tested in the animal model of dm with atherosclerotic lesions , and was shown to suppress the development of these lesions in the apo e null mice diabetic model . in another study , the administration of s - rage to diabetic c57/bj6 and rage - transgenic mice with diabetic symptoms inhibited blood - retinal barrier breakdown and leukostasis , which are the signs of retinopathy in diabetic patients . these studies suggested an anti - ageing characteristic for s - rage in ageing - related diseases . the rage : a transporter of amyloid beta in alzheimer disease 
  deposition of amyloid beta ( a ) as a senile plaque in the brain and the soluble oligomer form of a have been identified as one of the major causes of ad . salminen et al , mentioned that  full - length rage was expressed in astrocytes , microglia and neurons . it is known that the blood brain barrier is important for a brain balance , and that it regulates the transport of a through two receptors : the low density lipoprotein receptor related protein 1 and rage . the rage protein mediates the influx of amyloid protein from plasma to the brain , whereas , lrp protein mediates the efflux of amyloid protein through the bbb . deane et al , suggests that brain csf is separated from blood by tight junction between endothelial cells . therefore , a peptide movement through bbb needs a receptor such as rage to transfer a from plasma to csf through endocytosis . generally , efflux which is mediated by lrp1 is greater than influx by rage . in ad , changes in rage expression might create an imbalance between the rates of influx and efflux of a peptide through the bbb . 
 the rage activation and biological consequences : inflammation , oxidative stress , cell survival and proliferation 
  the rage is found on the surface of different kinds of cells such as lymphocytes , leukocytes , macrophages / microglia / monocytes , astrocytes , neurons , smooth muscle cells and endothelial cells . the rage was shown to influence cell survival , cell proliferation , oxidative stress and inflammatory responses . such a blockade shows that ages have effect on cell proliferation and cell survival through rage . moreover , several studies demonstrated a role for ages in the over - production of intracellular reactive oxygen species , impairments in proteasomal activities , inflammatory responses , and cell insensitivity to insulin in dm . on the other hand , ages can induce nitric oxide ( no ) production in retinal neurons and n-11 cell line . the product of this enzyme activation is superoxide ion , another ros . on the other hand , interaction of ligands with rage induces the production of cytokines followed by upregulation of multiple signalling pathways . ligand - induced rage activation is shown to drive nf-b expression , followed by upregulation of inflammatory markers and adhesion molecules , and consequently inflammatory cell recruitment to the site of inflammation . this migration may play an important role in the rage - mediated inflammatory responses in ad patients in the brain . c - reactive protein ( crp ) is a key marker of inflammation in cardiovascular diseases , and is a mediator for developing atherosclerosis . c - reactive protein increases the expression of cell adhesion molecules , chemokines , rage and the production of ros . they also demonstrated that this upregulation could be reduced by mapks inhibitors ; therefore , they suggested that p38 , erk and jnk signalling pathways were involved in crp - induced rage expression . donato et al , highlighted , in a review article , that s100b , an endogenous rage ligand , had protective and neurotrophic effects during brain development in low concentrations . moreover , in higher concentrations it had a toxic effect , which was through the production of ros in neuron in a rage - dependent manner . he also suggested that s100b - rage interaction could stimulate pro - inflammatory responses and ros production in monocytes / microglia / macrophages . cyclooxygenase is an enzyme responsible for the formation of prostanoids , and its role in inflammation has been pointed out by increasing evidence . this upregulation was also reported in cultured thp-1 monocytes and human peripheral blood monocytes stimulated by ages and s100b . it was shown that rage-/- mice in comparison with wild type ( wt ) , have a lower level of tnf- and il-6 plasma concentrations in response to hmgb1 stimulation . on the other hand , a high level of circulating tnf- was reported as a crucial mediator in rage / age and nf-b signalling pathway . prostaglandin f2 comprises a class of biologically active products of the arachidonic acid pathway , and is considered a marker of oxidative stress . relevance of urinary 8-iso - pgf2 with s - rage in diabetic patients has been considered . it was reported that pgf2 was high and had inverse correlation with s - rage plasma level . furthermore , the overproduction of intracellular ros was observed in thp1 monocytes after treatment with glycoxidized albumin . moreover , human umbilical vein endothelial cells ( huvecs ) induced by tnf- have demonstrated a high level of rage expression . this expression was reduced by n - acetyl - l - cysteine , a ros scavenger . e - selectin is a cell adhesion molecule , which is expressed in activated endothelial cells in inflammatory conditions and by ages . it has been reported that e - selectin was unregulated in human saphenous vein endothelial cells in response to heterogeneous ages . it was observed that e - selectin expression induced by glc - human serum albumin ( ghsa ) was reduced by nadph oxidase inhibitors and scavengers of ros , nac in human saphenous vein endothelial cells . however , it was reported that such e - selectin expression could not be abolished by anti - rage antibody . this information suggests that rage / age interaction stimulates pro - inflammatory responses through nf-b signalling pathway in an oxidative stress- dependent manner . 
 the rage and signaling pathways 
  nuclear factor kappa b ( nf-b ) and mapks such as erk1/2 , jnk , akt and p38 it was shown that s100a8 and s100a9-induced human prostate cancer cells could activate nf-b transcription in vivo . sun et al , showed that phosphorylated p38 was not associated with a plaques and neurofibrillary tangles in subregions of hippocampus of patients with ad . this suggests that p38/mapks signalling pathway is not crucial for the neurotixicity of a , which is a rage ligand . moreover , p38 mapk phosphorylation increased in cultured neurons treated with a nontoxic concentration of a42 , soluble amyloid beta peptide . further studies are in need to examine the role of pp38 in the rage signalling pathway . increase in the expression level of cox-2 , which was induced by s100b , another rage ligand , was reported in human peripheral blood monocytes from healthy donors . moreover , the involvement of nf-b in the expression of cox-2 induced by il-1 in mesenchymal cells of human amnion was shown . these studies implied that the role of cox-2 in the inflammatory response was rage - ligand dependent through nf-b signaling pathway . these studies are controversial , and more investigations are in need to examine the role of cox-2 in the rage signalling pathway . the proliferation of the mouse microglial cell line ra2 was stimulated through increasing the expression of macrophage colony - stimulating factor in a treated cell line . furthermore , an electromobility shift assay showed that the m - csf promoter region with a putative nf-b binding site was associated with a-induced m - csf expression in the ra2 cells treated with a. this gives an indication that a , a rage ligand , might act through the rage and akt / nf-b signaling pathway . the proposed schematic age - rage signalling pathways , are shown in figure 3 . potential therapeutic approaches according 
  to the ages hypothesis 
  a number of therapeutic approaches were proposed for ageing - related diseases with relevance to glycated proteins . these approaches include the use of age inhibitors , age breakers , age signalling blocking , anti - rage antibody and rage antagonists , and antioxidants such as ascorbic acid and -tocopherol ( vitamin e ) . anti - rage antibody treatment in uremic apoe/ mice showed a decrease in the development of atherosclerotic lesions . moreover , vitamin c treatment of patients with renal failure showed a decrease in ages plasma level . oxidative stress and ros production , based on the ages hypothesis , may potentially benefit from antioxidant treatment , especially in ad . inflammation induced by glycated proteins , interferon gamma and lipopolysaccharide 
  it has been reported that glycated proteins trigger the inflammation . the pathophysiology of inflammation includes the recruitment of white blood cells and production of cytokines which are the messenger among the cells . in addition , lipopolysaccharide ( lps ) , which is the outer membrane of gram negative bacteria , elicits the production of a number of cytokines . an excessively elevated level of cytokines was observed in ad patients . among those , inf- , which was originally called macrophage - activating factor , is of potential interest . macrophages are sensitive to inf-. in addition , the non lethal dose of lps was shown to be toxic in combination with inf- in mice . the involvement of cytokines with lps in shwartzman - like lethal inflammatory response was observed in rabbits and mice . there is evidence that this protein modification results in the elevated level of cytokines . inhibition of glycated protein induced - inflammation by different antioxidants 
  inflammation is known as a potential cause of neurodegenerative diseases such as ad and parkinson s . microglia , the resident macrophages in the brain , can produce inflammation markers such as no and tnf-. the inflammation , which results in neurodegenerative diseases , has a deleterious effect on neurons . polyphenols are a group of compounds with defined structures and are abundant in fruit and vegetables . the flavone structure is known as the antiinflammatory structure in a wide range of plant extracts . resveratrol ; however , belongs to a different structural family of plant extracts , and has stilbene structure ( figure 4 ) . the chemical structures of apigenin and resveratrol , their core structures , and related chemical groups are shown in figure 4 . inhibition of age - induced inflammation by compounds acting on the receptors 
  protein glycation is a protein modification , and is observed in ageing . there are various ways to intervene at the receptor level in age - rage signalling pathway such as the blockade of the receptor by antagonist and antibody . blockade of rage - ligand interaction by soluble rage , rage antibody and rage antagonist were considered in the reduction of plaque formation . any intervention along this signalling pathway could reduce the inflammation and consequently , induce damages . the chemical structures of apigenin and resveratrol ( a and c ) , the core structures and related chemical groups ( b and d ) . in addition , naturally occurring biopolymers such as hyaluronic acid is shown to have antagonizing activity . in addition to chemicals and polymers as antagonists for rage , antibodies against the receptor can be an alternative way of antagonizing the receptor . inhibition of age - induced inflammation by catalase , nadph oxidase inhibitors 
  the physiological role of no signalling as an extracellular signalling molecule is now widely appreciated . hydrogen peroxide ( h2o2 ) is another messenger with similar biochemical characteristics similar to no , and is predominantly involved in pro - inflammatory signalling . hydrogen peroxide can act as a messenger and transmit pro - inflammatory signals between adjacent cells . it can act both as a mediator molecule and a toxic substance . in higher concentrations the special role of h2o2 in inflammation by some types of cells such as t - cells has been extensively investigated . hydrogen peroxide belongs to ros , and it has been hypothesised that h2o2 acts as a messenger in gene regulation and signal transduction pathways . it has also been reported that the concentration of h2o2 in leukocytes increases from 1 to 100 mm during phagocytosis . schematic presentation of the chemical reactions involved in antioxidant defense mechanisms , are shown in figure 5 . while there are several studies about glycated proteins , the number of reports regarding the signalling network triggered by glycated proteins is limited . the publications reviewed herein might indicate that age - rage signalling pathway was a possible signalling pathway . in addition to inflammatory response , oxidative stress is another mechanism through which the destructive effects of glycated protein in ad and other age - related diseases are prominent . it is still unclear what the second messenger of the rage , which results in the receptor activation , is . it might also be possible to conclude that the understanding of the pathway can help in finding an inhibitory compound useful in ad
glycation is a protein modification , which results in a change in a protein structure . 
 glycation is believed to be the etiology of various age - related diseases such as diabetes mellitus and alzheimer s disease ( ad ) . 
 activation of microglia and resident macrophages in the brain by glycated proteins with subsequent oxidative stress and cytokine release may be an important factor in the progression of ad . 
 it is also suggested that interaction between an advanced glycation end product ( age ) and its receptor ( rage ) results in glial activation as well as cytokine release and reactive oxygen species release . 
 the use of antioxidants , receptor mediated compounds and reactive oxygen species scavenging enzyme produce an opportunity to intervene with age - rage signaling pathway , and thereby to slow down the progression of aging - related diseases .