review article role of methylglyoxal in alzheimer s...

Review ArticleRole of Methylglyoxal in Alzheimerrsquos Disease

Cristina Angeloni1 Laura Zambonin2 and Silvana Hrelia1

1 Department for Life Quality Studies Alma Mater Studiorum University of Bologna Corso drsquoAugusto 237 47900 Rimini Italy2 Department of Pharmacy and Biotechnology Alma Mater Studiorum University of Bologna Via Irnerio 48 40126 Bologna Italy

Correspondence should be addressed to Cristina Angeloni cristinaangeloniuniboit

Received 13 December 2013 Revised 28 January 2014 Accepted 30 January 2014 Published 9 March 2014

Academic Editor Tullia Maraldi

Copyright copy 2014 Cristina Angeloni et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Alzheimerrsquos disease is the most common and lethal neurodegenerative disorder The major hallmarks of Alzheimerrsquos diseaseare extracellular aggregation of amyloid 120573 peptides and the presence of intracellular neurofibrillary tangles formed byprecipitationaggregation of hyperphosphorylated tau protein The etiology of Alzheimerrsquos disease is multifactorial and a fullunderstanding of its pathogenesis remains elusive Some years ago it has been suggested that glycation may contribute to bothextensive protein cross-linking and oxidative stress in Alzheimerrsquos disease Glycation is an endogenous process that leads to theproduction of a class of compounds known as advanced glycation end products (AGEs) Interestingly increased levels of AGEshave been observed in brains of Alzheimerrsquos disease patients Methylglyoxal a reactive intermediate of cellular metabolism is themost potent precursor of AGEs and is strictly correlated with an increase of oxidative stress in Alzheimerrsquos disease Many studiesare showing that methylglyoxal and methylglyoxal-derived AGEs play a key role in the etiopathogenesis of Alzheimerrsquos disease

1 Introduction

Alzheimerrsquos disease (AD) is themost common and lethal neu-rodegenerative disorder characterized by progressive neu-ronal loss and neuroinflammation in the brain and associatedwith progressive cognitive decline memory impairment andchanges in behavior and personality with rising incidenceamong elderly people One of the pathological hallmarks ofAD is neuritic plaques in the cerebral cortex and hippocam-pus Amyloid 120573 (A120573) a 40ndash42 amino-acid peptide generatedby proteolytic cleavages of the amyloid-120573 protein precursor(APP) [1] is one of the main components of neuritic plaquesA120573 is cytotoxic and capable of inducing oxidative stress andneurodegeneration [2 3] Another distinctive feature of ADis neurofibrillary tangles (NFTs) composed of bundles ofpaired helical filaments (PHFs) [4] mainly containing hyper-phosphorylated microtubule-associated tau protein (MAP-tau) [5] Under normal physiological conditions tau pro-motes assembly and stability of microtubules and is thusinvolved in axonal transport [6 7] In AD tau proteinsaggregate forming fibrillar insoluble intracellular inclusions

Themain processes involved in the etiology and pathogenesisof AD are reported in Figure 1

The full understanding of the etiology and pathogenesisofADhas remained elusive andmore andmore evidences areconfirming that AD is a disease with numerous genetic andenvironmental contributing factors Some years ago it hasbeen proposed that a chemical process known as glycationmay contribute to both extensive protein cross-linking andoxidative stress in AD [8] Nonenzymatic protein glycationis an endogenous process in which reducing sugars reactwith amino groups in proteins through a series of Maillardreactions forming reversible Schiff base and Amadori com-pounds producing a heterogeneous class of molecules col-lectively termed advanced glycation end products (AGEs) [9]The 120572-ketoaldehyde methylglyoxal (MG) formed endoge-nously as a by-product of the glycolytic pathway by degra-dation of triosephosphates or nonenzymatically by sugarfragmentation reactions is themost potent precursor of AGEformation [10] MG is able to induce cellular damage cross-linking of proteins and glycation [11] playing an importantrole in the pathogenesis of many neurodegenerative diseases

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 238485 12 pageshttpdxdoiorg1011552014238485

2 BioMed Research International

TauTau

Vascularabnormality

Amyloidplaque

ApoE4

A120573

A120573-degradingenzyme

Microglial cell

Oligomers

Impairedsynapse

Neurofibrillarytangles

Figure 1 Classical processes participating in the etiology and pathogenesis of AD (modified from [131])

[12] In AD AGEs accumulate in neurons and astroglia andare also found associated with neuritic amyloid plaques andNFTs [13ndash16] MGmay also contribute to neurodegenerationtriggering oxidative stress [17ndash19] Oxidative stress is char-acterized by an imbalance between reactive oxygen species(ROS) production and the detoxifying endogenous systemThere is accumulating evidence suggesting a key role ofoxidative stress in the pathophysiology of AD [20ndash23] Acentral role for oxidative stress by the activation of NADPHoxidase in astrocytes has been demonstrated as the causeof A120573-induced neuronal death [24] and of alterations inastrocyte mitochondrial bioenergetics that may in turn affectneuronal functioning andor survival [25]

As oxidative stress and MG are closely interlinked therole ofMG andMG-induced production of AGEs and ROS inthe development of AD is reviewed in this paper In additionthe ability of MG to modulate detrimental redox signaling inAD has been considered

2 Methylglyoxal Production

MG is a reactive intermediate of cellular metabolism presentubiquitously in all cells It is produced under both normaland pathological conditions via several different pathwaysinvolving both enzymatic and nonenzymatic reactions [26]The rate of MG formation depends on the organism tissuecell metabolism and physiological conditions therefore MGplasma concentration reflects these factors Plasmatic MGcan be derived from exogenous sources such as coffeealcoholic beverages and food [27 28] and from endogenoussources in situ formation in the plasma release from cellsand loss from injured cells [29]

Since MG is ubiquitously present in living cells almostall foods and beverages contain MG as reviewed by Vistoli etal [30] The main sources of MG are represented by mono-

oligo- and polysaccharides and lipids [31] Several reactionsand processes are involved in the accumulation of MGautoxidation photodegradation and heating and prolongedstorage are the main sources of MG as a degradation productin foodstuff [32ndash35] Moreover many microorganisms pro-duce and release MG fermentation can be a critical processincreasingMG levels in alcoholic drinks and fermented foods[36] MG is reported to originate also from environmentalsources Cigarette smoke is one of the combustion processesthat can generate MG [37] drinking water can contain MGdue to the purification treatments [38] rainwater can absorbMG from polluted air and transmits it to the soil [39]

Endogenously derived MG is formed during carbohy-drate and lipid and amino acid metabolisms and involvesboth enzymatic and nonenzymatic reactions [40ndash43] Theenzymes that catalyze the reactions of MG synthesis areMG synthase cytochrome P450 2E1 myeloperoxidase andamino oxidase participating in glycolytic bypass ace-tone metabolism and amino acid breakdown respectivelynonenzymatic pathways include the spontaneous decompo-sition of dihydroxyacetone phosphate the Maillard reactionthe oxidation of acetol and lipid peroxidation [42]

The main pathway leading to MG is linked to carbohy-drate metabolism and involves enzymatic and nonenzymaticdegradation of the triosephosphate intermediates glyceralde-hyde 3-phosphate and dihydroxyacetone-phosphate deriv-ing from glycolysis [40 44 45] It should be noted thattriosephosphates originate not only from glycolytic processesbut also from other routes of glucose metabolism (Entner-Doudoroff pathway hexose monophosphate route) and fromxylitol metabolism or the activity of glycerophosphate dehy-drogenase linking glycerol breakdown to MG production[40] Dihydroxyacetone phosphate can be converted to MGby either spontaneous nonenzymatic elimination of thephosphate group or by the enzymatic contribution of MG

BioMed Research International 3

synthase an enzyme found in prokaryotic and mammaliansystems [36 46]MG can also derive via theMaillard reactionin vivo under physiological conditions similar to what isobserved during food cooking and through the glycation ofmacromolecules and the autoxidation of carbohydrates [43]

MG production deriving from lipidmetabolism ismainlylinked to the acetone metabolism [47] Acetone is derivedfrom acetoacetate by myeloperoxidase activity and is con-verted to MG by the cytochrome P450 2E1 via acetol asintermediate [48] In pathological conditions like ketosisand diabetic ketoacidosis the oxidation of ketone bodies islikely to be an important source of MG [49] In additiontriacylglycerol hydrolysis produces glycerol that can be trans-formed into MG through glycerolphosphate produced bya specific glycerol kinase [50] Lipoperoxidation is anothernonenzymatic process leading to MG formation [51 52]

The catabolism of the aminoacids threonine and glycine(and partially tyrosine) can also generate MG through theaminoacetone intermediate [53ndash55]Thismetabolic oxidativepathway is mediated by the enzyme semicarbazide sensitiveamine oxidase (SSAO) and appears to be exacerbated in lowcoenzyme A states [56 57]

3 Methylglyoxal Induced AGE Production

MG is able to induce protein glycation leading to theformation of AGEs [11] and is believed to be the mostimportant source of AGEs Glycation of proteins is acomplex series of parallel and sequential reactions known asMaillard reaction [58] Glycation starts with the reaction ofglucose with lysine and leads to the formation of fructosyl-lysine (FL) and N-terminal amino acid residue-derivedfructosamines while later stage reactions produce stableadducts [58] It has been observed that FL degrades slowlyto form AGEs [59] while MG reacts relatively rapidly withproteins to form AGEs [58] in particular MG is up to 20000times more reactive than glucose in glycation reactions[11] MG reacts almost exclusively with arginine residuesand to a lesser extent with lysine cysteine and tryptophanresidues The reaction of MG with arginine leads to theformation of cyclic imidazolone adducts (MG-H) [60] andother related structural isomers MG-H is formed as threestructural isomers N120575-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) 2-amino-5-(2-amino-5-hydro-5-methyl-4-imidazolon-1-yl)pentanoic acid (MG-H2) and2-amino-5-(2-amino-4-hydro-4-methyl-5-imidazolon-1-yl)pentanoic acid (MG-H3) [61] These adducts can undergoother reactions they can add a secondMGmolecule yieldingeither N120575-(4-carboxy-46-dimethyl-56-dihydroxy-1456-tetrahydropyrimidine-2-yl)-L-ornithine (THP) [62] or arg-pyrimidine (N120575-(5-hydroxy-46-dimethylpyrimidine-2-yl)-l-ornithine) [63] MG also reacts with lysine residues to formthe N

120576-(1-carboxyethyl)-L-lysine (CEL) and N

120576-(1-carbo-

xymethyl)-L-lysine (CML) adducts and the lysine dimer 13-di(N120576-lysino)-4-methyl-imidazolium (MOLD) [64] With

one lysine and one arginine residue MG forms 2-ammo-nio-6-(2-[(4-ammonio-5-oxido-5-oxopentyl) amino]-4-me-thyl-45-dihydro-1H-imidazol-5-ylidene amino) hexanoate(MODIC) [65] MG can react also with cysteine residues

giving reversible hemithioacetal adducts [66] and couldspontaneously modify tryptophan residues yielding 120573carboline derivatives [33]

In human serum albumin the following concentra-tions of MG-derived AGEs were detected MG-H1 2493 plusmn87mmolmol protein argpyrimidine 200 plusmn 40mmolmolprotein CEL 297 plusmn 18mmolmol protein and MOL 5 plusmn1mmolmol protein [67] In cerebrospinal fluid of patientswith amyotrophic lateral sclerosis elevated levels of CMLwere reported [68] and the tissue levels of CML in corticalneurons and cerebral vessels were related to the severityof cognitive impairment in patients with cerebrovasculardisease [69] It has been demonstrated that MG is involvedin the increased levels of AGEs observed in AD [70] andMG-derived AGEs such as CEL andMOLD andMG-derivedhydroimidazolone have each been identified in intracellularprotein deposits in neurofibrillary tangles [71] and cere-brospinal fluid [72]

4 Methylglyoxal Induced ROS Production

The production of ROS and reactive nitrogen species (RNS)during MG metabolism have been extensively depicted insome reviews [43 73 74] and a large body of literaturedescribes the correlation among MG AGEs oxidative stressand pathologies [40] such as diabetes [75] hypertension [76]aging [74 77 78] and neurodegeneration [13 79]

Although the link betweenMG and free radicals has beeninvestigated since the 1960smainly by Szent-Gyorgyi [80 81]only in 1993 the generation of ROS in a cellular system wasdescribed [82]

Free radicals andor ROS and RNS can be producedduring both the formation of MG and its degradation thereactions involved in these processes could be summarized asfollowsThe enzymatic formation of MG from aminoacetone(catalyzed by SSAO) or from acetol (catalyzed by galactoseoxidase) is coupled to hydrogen peroxide production [83 84]hydrogen peroxide is produced also whenMG is converted topyruvate by the action of the enzyme glyoxal oxidase [85 86]The autoxidation of aminoacetone toMG mediated by metalions such as Fe2+ and Cu2+ is considered a source of carbon-centered radicals and superoxide [87 88] similarly thenonenzymatic reaction from acetoacetate to MG producesROS in the presence of myoglobin hemoglobin manganesecytochrome c or peroxidase [89 90]

MG likewise for monosaccharide undergoes autoxida-tion [91ndash93] and photolysis [94] resulting in ROS generationthese reactions involve superoxide hydrogen peroxide andhydroxyl radical [95]

As reported in [43] and [77] ROS production relatedto MG has been identified in a very wide range of cellularsystems for example vascular smoothmuscle cells (VSMCs)endothelial cells rat hepatocytes platelet neurons and soforth We have recently demonstrated that MG induces ROSproduction in primary culture of rat cardiomyocytes [96]

Moreover MG is able to increase the activity of prooxi-dant enzymes [97ndash99] and to reduce antioxidants in particu-lar glutathione (GSH) and its enzymes [17 100 101] Since theglyoxalase system that degradesMGuses reduced glutathione


as a cofactor [102] decreased antioxidants in turn impair thedetoxification of MG leading to further oxidative damage

It has been reported furthermore that MG can mod-ify CuZn superoxide dismutase (SOD) by covalent cross-linking releasing copper ions from the enzyme and inac-tivating it [103] Other studies indicate that MG increasesmitochondrial superoxide production [104 105]

The correlation between ROS levels and MG concentra-tion has been reported both in animals and cultured cells[43 76 77] Commonly in cell models the administration ofMG to the medium is followed by ROS level determinationthat is often obtained by the 2101584071015840-dichlorodihydrofluoresceindiacetate (DCFH-DA) assay or seldom by other tests such aslucigenin-linked chemiluminescence assay [106]

As previously reported MG is the most reactive endoge-nous carbonyl able to generate AGEs AGEs also induceoxidative stress through several mechanisms AGEs stimulateproduction of cytokines and growth factors [62 66 107ndash111] Moreover AGEs bind to the AGE receptor (RAGE) andscavenger receptors to induce oxidative stress in various cellsincludingVSMCs endothelial cells andmononuclear phago-cytes [112] In endothelial cells AGEs increase expressionof vascular cell adhesion molecule-1 (VCAM-1) intercellu-lar adhesion molecule-1 (ICAM-1) and increase activity ofnuclear factor kappa light chain enhancer of activated B cells(NF-120581B) to increase oxidative stress [109 113]

5 Methylglyoxal and Methylglyoxal-DerivedAGE Deposits in AD

As both the extracellular A120573 deposits and the intracellularNFTs have elevated stability and are long-lived proteinsthey represent an ideal substrate for glycation [70] It hasbeen suggested that the insolubility and protease resistanceof 120573-amyloid plaques are caused by extensive AGE-covalentprotein cross-linking [4 16] In 1994 Vitek et al observed forthe first time that plaque fractions of AD brains containedabout 3-fold more AGE adducts than preparations fromhealthy age-matched controls They showed that the invivo half-life of 120573-amyloid is prolonged in AD resulting ingreater accumulation of AGE modifications which in turnmay act to promote accumulation of additional amyloid[114] An immunohistochemical study using a monoclonalantibody specific for AGE proteins showed extracellular AGEimmunoreactivity in amyloid plaques in different corticalareas in particular primitive plaques coronas of classicplaques and some glial cells in AD cortex were positive forAGEs [115]More recently Fawver et al [14] stained AD braintissue for AGEs and similar to the previous findings AGEswere colocalized with amyloid plaques In addition Ko et al[116] showed that APP was upregulated by AGEs in vitro andin vivo andAGEsmodulateAPP expression throughROS Toexplore whether glycated A120573 is more toxic than authentic A120573Li et al [117] treated 8-DIV embryonic hippocampal neuronswith A120573 or A120573-AGE for 24 h They found that A120573-AGE wasmore toxic than A120573 in decreasing cell viability increasing cellapoptosis inducing tau hyperphosphorylation and reducingsynaptic proteins It has also been observed that MG is not

only capable of increasing the rate of production of120573-amyloid120573-sheets oligomers and protofibrils but also of increasing thesize of the aggregates [13]

The 1205764 allele of the apolipoprotein E (ApoE) is knownas an important susceptibility gene for AD [118 119] It hasbeen demonstrated thatApoE is codeposited in senile plaquesin brains of patients with AD [120] and ApoE4 carrierspresent a higher A120573 deposition in the form of senile plaquesthan noncarriers [121 122] Interestingly AGEs colocalizedto a very high degree with ApoE and ApoE4 exhibited a 3-fold greater AGE-binding activity than the ApoE3 isoform[123] The authors suggested that ApoE may participate inaggregate formation in the AD brain by binding to AGE-modified plaque components whichmay explain whyApoE4is associated with increased risk of AD

As discussed above AGEs can be localized intracellularlyEvidences have been provided that AGEs may accumulate inpyramidal neurons exhibiting a granular perikaryonal distri-bution in human brain whereas animals show a nuclear stain-ing pattern [124] It has been shown that AGEs accumulatein endosomal and lysosomal vesicles of pyramidal neuronsin the hippocampus the dentate gyrus cortical layers III Vand VI and in entorhinal cortical layers II III V and VI[125] Interestingly Wong et al [126] observed colocalizationof AGEs and inducible nitric oxide synthase (iNOS) in a fewastrocytes in the upper neuronal layers in the early stage ADbrains while in late AD brains there was a much denseraccumulation of astrocytes colocalized with AGEs and iNOSin the deeper and particularly upper neuronal layers Animmunohistochemical study showed that in ADpatients thepercentage of AGE-positive neurons (and astroglia) increaseswith the progression of the disease and those neurons whichshow diffuse cytosolic AGE immunoreactivity also containhyperphosphorylated tau suggesting a link between AGEaccumulation and the formation of early neurofibrillarytangles [16] Using specific AGE antibodies directed againstCML pyrraline and hexitol-lysine it has been demonstratedthat AGEs are colocalized with NFTs [15 127 128]

In AD patients AGEs accumulate also in the cere-brospinal fluid (CSF) which is in close contact with thebrain An increased accumulation of Amadori products inall major proteins of CSF of AD patients including albuminapolipoprotein E and transthyretin has been observed [129]Bar et al [130] measured significantly elevated levels of CMLin CSF of AD patients when compared to controls In CSFprotein Ahmed et al [72] observed an increased levels ofCML residues in subjects with AD and in CSF ultrafiltratethe concentrations of MG-derived hydroimidazolone freeadducts were also increased

6 Role of Methylglyoxal and Methylglyoxal-Derived AGEs in the Progression of AD

The process underlying AD is complex and involves manydifferent features such as mitochondrial dysfunction abnor-mal protein aggregation inflammation and excitotoxicityBeeri et al [132] conducted an interesting clinical study on267 subjects at least 75 years old and cognitively intact at


the beginning of the project They demonstrated that thesubjects with higher serum levels of MG had a faster rate ofcognitive decline Several potential mechanisms have beensuggested to explain MG and MG-derived AGE neurotoxi-city Krautwald and Munch [70] suggested that AGEs con-tribute to the pathogenesis of AD in two different ways cross-linking cytoskeletal proteins inducing neuronal dysfunctionand death and accumulating on A120573 deposits chronicallyactivating micro- and astroglial cells as widely underlinedin the previous paragraph Moreover it has been observedthat MG is a neurotoxic mediator of oxidative damage inthe progression of AD and other neurodegenerative diseases[133] The brain is highly susceptible to oxidative stress dueto its high energy demand high oxygen consumption largeamounts of peroxidizable polyunsaturated fatty acids andlow levels of antioxidant enzymes [134] It is no wonder thatROS induced damage to biomolecules is widely reported inAD and increasing evidences suggest that oxidative stressplays a critical role in the disease [135] As the impairment ofmitochondrial function is themain source of ROS generationand also a major target of oxidative damage mitochondrialdysfunction has been implicated in AD [136 137] de Arribaet al [138] demonstrated that MG may seriously affectmitochondrial respiration and the energetic status of cellsIn particular they observed that MG increases intracellularROS and lactate production in SH-SY5Y neuroblastomacells and decreases mitochondrial membrane potential andintracellular ATP levels SH-SY5Y neuroblastoma cells havebeen extensively used to study the effect of MG as theyshow greater sensitivity to MG challenge due to a defectiveantioxidant and detoxifying ability [17] Huang et al [139]observed thatMG inducedNeuro-2A neuroblastoma cell lineapoptosis via alternation of mitochondrial membrane poten-tial and BaxBcl-2 ratio activation of caspase-3 and cleavageof poly(ADP-ribose) polymerase (PARP) Moreover theyinvestigated the mechanisms behind MG-induced neuronalcell apoptosis demonstrating that MG activates proapoptoticmitogen-activated protein kinase (MAPK) signaling path-ways (JNK and p38) This data is in agreement with theresults of Chen et al [140] that using primary cultures of rathippocampal neurons demonstrated that MG increases theexpression level of cleaved caspase-3 and decreases Bcl-2Baxratio As activated caspase-3 immunoreactivity is elevated inAD and exhibits a high degree of colocalization with NFTsand senile plaque in AD brain it has been suggested thatactivated caspase-3may be a factor in functional decline [63]

AGEs exert direct toxicity to cells through predominantlyapoptotic mechanisms Yin et al [141] investigated the effectsof AGEs in SH-SY5Y cells and rat cortical neurons Theyobserved that AGEs induce cell death increasing intracellu-lar ROS through the increase of NADPH oxidase activityMoreover endoplasmic reticulum stress was triggered byAGE-induced oxidative stress resulting in the activation ofCEBP homologous protein (CHOP) and caspase-12 thatconsequently initiates cell death Tau phosphorylation isstrictly controlled by the coordinated activities of tau phos-phatase(s) and tau kinase(s) and the hyperphosphorylationof tau in the AD brain might be due to the overactiveprotein kinases andor inactivation of protein phosphatases

[142 143] Tau can be phosphorylated by different proteinkinases such as the members of the MAPK family (JNKp38 and Erk12) GSK-3120573 and cyclin-dependent kinase 5(cdk5) while protein phosphatase (PP) 2A plays a major rolein regulating dephosphorylating of the hyperphosphorylatedtau isolated from the AD brains [143ndash147] Using wild-typemouse N2a cells Li et al [148] observed that MG inducestau hyperphosphorylation and activates GSK-3120573 and p38while the simultaneous inhibition of GSK-3120573 or p38 couldattenuateMG-induced tau hyperphosphorylation suggestingan important roles of GSK-3120573 and p38 in the MG-inducedNTFs formationOn the other hand an interesting proteomicstudy demonstrated a decreased level of PP2 in SH-SY5Ycells subjected to MG-induced oxidative stress Thus itcould be speculated that MG has a double role in inducingtau hyperphosphorylation enhancing kinase activities andreducing phosphatase level Besides hyperphosphorylationit has been suggested that carbonyl-derived posttranslationalmodifications of neurofilaments may account for the bio-chemical properties of NFTs likely as a result of extensivecross-links [149 150] Kuhla et al [151] in an in vitro experi-ment incubated wild-type and seven pseudophosphorylatedmutant tau proteins with MG and observed the formationof PHF-like structures Interestingly MG formed PHFs in aconcentration-dependent manner and this process could beaccelerated by hyperphosphorylation

7 Redox Signaling Modulated byMethylglyoxal in AD

As previously highlightedMG cytotoxicity to tissue or cells ismainly mediated through an increase of oxidative stress andan induction of apoptosis Oxidative stress is thought to playa causative role in the development of AD [152 153] Suchstress is a typical activator of two important MAPK pathwaysin AD the JNK and the p38 signaling pathways [154] It hasbeen suggested that the activation of the MAPK signalingpathways contributes to AD pathogenesis through differentmechanisms including induction of apoptosis in neurons[155ndash158] activation of 120573- and 120574-secretases [159 160] andphosphorylation and stabilization of APP [161 162] Differentstudies have associated MG with MAPK pathways In RAW2647 cells MG stimulated the simultaneous activation ofp4442 and p38 MAPK and also stimulates the translocationto the cell membranes of another important protein kinaseinvolved in cellular signaling protein kinase C (PKC) [163]Moreover Pal et al [164] indicated that MG stimulates iNOSactivation by p38 MAPK-NF-120581120573-dependent pathway andROS production by ERK and JNK activation in sarcoma-180tumor bearing mice

Regarding the implications of MAPK signaling pathwayin oxidative damage leading to apoptosis it has been observedthat MG is able to induce apoptosis in PC12 cells throughthe phosphatidylinositol-3 kinaseAktmammalian target ofrapamycingamma-glutamylcysteine ligase catalytic subunit(PI3KAktmTORGCLc)redox signaling pathway Huang etal [165] indicated that MG-induced Neuro-2A cell apoptosiswas mediated through activation of the MAPK signaling


NADPH oxidase activity

Oxidativestress

JNK ERK p38 MAPK

Apoptosis

ActivationInhibitionProduction

MG

GSK-3120573 PP2

NFTs

Tau-hyperphosphorylation

AGEs

Glycated

Glycated

NFTs

APP

A120573-deposit

A120573-deposit

Astroglial cells

Microglial cells

Synapticproteins

Figure 2 Role of MG and MG-derived AGEs in AD

pathway mediated by p38 and JNK Recently Heimfarth etal [166] demonstrated that the exposure of slices of cerebralcortex and hippocampus of new born rats to mM MGinduced ROS production and cytotoxicity In particular theyshowed that the signaling pathwaymediated by ERK is totallyimplicated in the ROS-mediated cytotoxic damage as theinitial blockage of MEKERK signaling pathway might beuseful for the protection of cells from the high ROS levelsAdditionally they observed that p38MAPK and JNKpathwayactivation is related with ROS-independent mechanismsleading to reduced cell viability and apoptotic cell death

Moreover as it has been underlined in the previousparagraph the MG activation of GSK-3120573 and p38 MAPKinduces AD tau hyperphosphorylation [148]

8 Conclusions

Many scientific evidences revealed different importantactions of MG on signal transduction redox balanceand cell energetic status as well as homeostatic control ofcellular function Elevated MG levels induce AGEs and ROSproduction playing a role in AD by several mechanisms(Figure 2) AGEs extensively cross-link proteins in A120573deposits and neurofilaments exacerbating AD pathologicalhallmarks In particular AGEs cross-link proteins in A120573deposits making them more insoluble protease resistantand more toxic MG induces tau hyperphosphorylation byenhancing kinase activities and reducing phosphatase levelMoreover MG is a neurotoxic mediators of oxidative stressin the progression of AD and is capable of activating many

redox signaling pathways leading to apoptosis and cellulardysfunction Accumulation of AGEs further magnifiesROS production by inducing the glycation of importantantioxidant enzymes and by providing precursor of oxidativestress In conclusion it can be reasonably supposed thatcognitive decline associated with AD might be stronglylinked to an increase in MG levels due to an oxoaldehydedetoxification impairment or an altered endogenousoxoaldehyde production From a clinical point of view thereduction of risk factors for pathologies such as diabetescharacterized by MG accumulation due to hyperglycemicconditions and impaired glucose metabolism [167] and theenhancement of MG scavenging system may provide newtherapeutic opportunities to reduce the pathophysiologicalmodifications associated with carbonyl stress in AD

Abbreviation List

AD Alzheimerrsquos diseaseAGEs Advanced glycation end productsApoE Apolipoprotein EAPP Amyloid-120573 protein precursorArgpyrimidine N120575-(5-Hydroxy-46-

dimethylpyrimidine-2-yl)-l-ornithine

A120573 Amyloid 120573cdk5 Cyclin-dependent kinase 5CEL N120576-(1-Carboxyethyl)-L-lysineCHOP CEBP homologous proteinCML N120576-(1-Carboxymethyl)-L-lysineCSF Cerebrospinal fluid


DCFH-DA 2101584071015840-Dichlorodihydrofluoresceindiacetate

FL Fructosyl-lysineGSH GlutathioneICAM-1 Intercellular adhesion molecule-1iNOS Inducible nitric oxide synthaseMAP-tau Microtubule-associated tau

proteinMAPK Mitogen activated protein kinaseMG-H Imidazolone adducts

(methylglyoxal-derived hydro-imidazolone)

MG-H1 N120575-(5-Hydro-5-methyl-4-imidazolon-2-yl)-ornithine

MG-H2 2-Amino-5-(2-amino-5-hydro-5-methyl-4-imidazolon-1-yl)pentanoic acid


MG MethylglyoxalMODIC 2-Ammonio-6-(2-[(4-ammonio-

5-oxido-5-oxopentyl)amino]-4-methyl-45-dihydro-1H-imidazol-5-ylideneamino) hexanoate

MOLD 13-Di(N120576-lysino)-4-methyl-imidazolium

NADPH Nicotinamide adeninedinucleotide phosphate

NF-120581B Nuclear factor kappa light chainenhancer of activated B cells

NFTs Neurofibrillary tanglesPARP Poly (ADP-ribose) polymerasePHFs Paired helical filamentsPI3KAktmTORGCLc Phosphatidylinositol-3

kinaseAktmammalian target ofrapamycingamma-glutamylcysteine ligase catalyticsubunit

PKC Protein kinase CPP Protein phosphataseRAGE Receptor for AGEsRNS Reactive nitrogen speciesROS Reactive oxygen speciesSOD Superoxide dismutaseSSAO Semicarbazide sensitive amine

oxidaseTHP N120575-(4-Carboxy-46-dimethyl-

56-dihydroxy-1456-tetrahydropyrimidine-2-yl)-L-ornithine

VCAM-1 Vascular cell adhesion molecule-1VSMCs Vascular smooth muscle cells

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by MIUR-FIRB (Project RBAP11-HSZS) and ldquoFondazione del Monte di Bologna e Ravennardquo(Italy) (Cristina Angeloni and Silvana Hrelia)

References

[1] H Zheng and E H Koo ldquoBiology and pathophysiology of theamyloid precursor proteinrdquo Molecular Neurodegeneration vol6 no 1 article 27 2011

[2] D M Walsh I Klyubin J V Fadeeva M J Rowan and D JSelkoe ldquoAmyloid-120573 oligomers their production toxicity andtherapeutic inhibitionrdquo Biochemical Society Transactions vol30 no 4 pp 552ndash557 2002

[3] D T Loo A Copani C J Pike E R Whittemore A JWalencewicz and C W Cotman ldquoApoptosis is induced by 120573-amyloid in cultured central nervous system neuronsrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 90 no 17 pp 7951ndash7955 1993

[4] A-L Bulteau P Verbeke I Petropoulos A-F Chaffotte andB Friguet ldquoProteasome inhibition in glyoxal-treated fibroblastsand resistance of glycated glucose-6-phosphate dehydrogenaseto 20 S proteasome degradation in vitrordquo The Journal ofBiological Chemistry vol 276 no 49 pp 45662ndash45668 2001

[5] P S Sachdev L Zhuang N Braidy andWWen ldquoIs Alzheimerrsquosa disease of the white matterrdquo Current Opinion in Psychiatryvol 26 no 3 pp 244ndash251 2013

[6] D W Cleveland S Y Hwo and M W Kirschner ldquoPurificationof tau a microtubule associated protein that induces assemblyof microtubules from purified tubulinrdquo Journal of MolecularBiology vol 116 no 2 pp 207ndash225 1977

[7] R Brandt and G Lee ldquoFunctional organization of microtubule-associated protein tau Identification of regions which affectmicrotubule growth nucleation and bundle formation in vitrordquoThe Journal of Biological Chemistry vol 268 no 5 pp 3414ndash3419 1993

[8] G Munch J Thome P Foley R Schinzel and P RiedererldquoAdvanced glycation endproducts in ageing and Alzheimerrsquosdiseaserdquo Brain Research Reviews vol 23 no 1-2 pp 134ndash1431997

[9] P Ulrich and A Cerami ldquoProtein glycation diabetes andagingrdquo Recent Progress in Hormone Research vol 56 pp 1ndash212001

[10] P J Thornalley ldquoPharmacology of methylglyoxal formationmodification of proteins and nucleic acids and enzymaticdetoxificationmdasha role in pathogenesis and antiproliferativechemotherapyrdquo General Pharmacology vol 27 no 4 pp 565ndash573 1996

[11] P J Thornalley ldquoDicarbonyl intermediates in the MaillardreactionrdquoAnnals of the New York Academy of Sciences vol 1043pp 111ndash117 2005

[12] R Ramasamy S J Vannucci S S D Yan K Herold S FYan and AM Schmidt ldquoAdvanced glycation end products andRAGE a common thread in aging diabetes neurodegenera-tion and inflammationrdquo Glycobiology vol 15 no 7 pp 16Rndash28R 2005

[13] K Chen J Maley and P H Yu ldquoPotential implications ofendogenous aldehydes in 120573-amyloid misfolding oligomeriza-tion and fibrillogenesisrdquo Journal of Neurochemistry vol 99 no5 pp 1413ndash1424 2006


[14] J N Fawver H E Schall R D P Chapa X Zhu andI V Murray ldquoAmyloid-beta metabolite sensing biochemicallinking of glycation modification and misfoldingrdquo Journal ofAlzheimerrsquos Disease vol 30 no 1 pp 63ndash73 2012

[15] R J Castellani P L R Harris L M Sayre et al ldquoActiveglycation in neurofibrillary pathology of Alzheimer diseaseN120576-(Carboxymethyl) lysine and hexitol-lysinerdquo Free RadicalBiology and Medicine vol 31 no 2 pp 175ndash180 2001

[16] H-J Luth V Ogunlade B Kuhla et al ldquoAge- and stage-dependent accumulation of advanced glycation end products inintracellular deposits in normal andAlzheimerrsquos disease brainsrdquoCerebral Cortex vol 15 no 2 pp 211ndash220 2005

[17] F Amicarelli S Colafarina F Cattani et al ldquoScavengingsystem efficiency is crucial for cell resistance to ROS-mediatedmethylglyoxal injuryrdquo Free Radical Biology and Medicine vol35 no 8 pp 856ndash871 2003

[18] S Kikuchi K Shinpo FMoriwaka ZMakita TMiyata and KTashiro ldquoNeurotoxicity ofmethylglyoxal and 3-deoxyglucosoneon cultured cortical neurons synergism between glycationand oxidative stress possibly involved in neurodegenerativediseasesrdquo Journal of Neuroscience Research vol 57 no 2 pp280ndash289 1999

[19] K Shinpo S Kikuchi H Sasaki A Ogata F Moriwaka andK Tashiro ldquoSelective vulnerability of spinal motor neuronsto reactive dicarbonyl compounds intermediate products ofglycation in vitro implication of inefficient glutathione systemin spinal motor neuronsrdquo Brain Research vol 861 no 1 pp 151ndash159 2000

[20] DA Butterfield andCM Lauderback ldquoLipid peroxidation andprotein oxidation in Alzheimerrsquos disease brain potential causesand consequences involving amyloid 120573-peptide-associated freeradical oxidative stressrdquo Free Radical Biology and Medicine vol32 no 11 pp 1050ndash1060 2002

[21] C E Cross B Halliwell E T Borish et al ldquoOxygen radicals andhuman disease Davis conferencerdquo Annals of Internal Medicinevol 107 no 4 pp 526ndash545 1987

[22] W R Markesbery ldquoOxidative stress hypothesis in Alzheimerrsquosdiseaserdquo Free Radical Biology and Medicine vol 23 no 1 pp134ndash147 1997

[23] A Tarozzi C Angeloni M Malaguti F Morroni S Hrelia andP Hrelia ldquoSulforaphane as a potential protective phytochemicalagainst neurodegenerative diseasesrdquo Oxidative Medicine andCellular Longevity vol 2013 Article ID 415078 10 pages 2013

[24] A Y Abramov L Canevari and M R Duchen ldquo120573-amyloidpeptides inducemitochondrial dysfunction and oxidative stressin astrocytes and death of neurons through activation ofNADPH oxidaserdquo Journal of Neuroscience vol 24 no 2 pp565ndash575 2004

[25] E Motori J Puyal N Toni et al ldquoInflammation-induced alter-ation of astrocyte mitochondrial dynamics requires autophagyfor mitochondrial network maintenancerdquo Cell Metabolism vol18 no 6 pp 844ndash859 2013

[26] M S Silva R A Gomes A E Ferreira A P Freire and CCordeiro ldquoThe glyoxalase pathway the first hundred yearsand beyondrdquo The Biochemical Journal vol 453 no 1 pp 1ndash152013

[27] I Nemet L Varga-Defterdarovic and Z Turk ldquoMethylglyoxalin food and living organismsrdquo Molecular Nutrition and FoodResearch vol 50 no 12 pp 1105ndash1117 2006

[28] J Wang and T Chang ldquoMethylglyoxal content in drinkingcoffee as a cytotoxic factorrdquo Journal of Food Science vol 75 no6 pp H167ndashH171 2010

[29] M P Kalapos ldquoWhere does plasma methylglyoxal originatefromrdquo Diabetes Research and Clinical Practice vol 99 no 3pp 260ndash271 2013

[30] G Vistoli D De Maddis A Cipak N Zarkovic M Cariniand G Aldini ldquoAdvanced glycoxidation and lipoxidation endproducts (AGEs and ALEs) an overview of their mechanismsof formationrdquo Free Radical Research vol 47 no S1 pp 3ndash272013

[31] J Degen M Hellwig and T Henle ldquo12-dicarbonyl compoundsin commonly consumed foodsrdquo Journal of Agricultural and FoodChemistry vol 60 no 28 pp 7071ndash7079 2012

[32] Y V Pfeifer P T Haase and LWKroh ldquoReactivity of thermallytreated alpha-dicarbonyl compoundsrdquo Journal of Agriculturaland Food Chemistry vol 61 no 12 pp 3090ndash3096 2013

[33] I Nemet and L Varga-Defterdarovic ldquoMethylglyoxal-derived120573-carbolines formed from tryptophan and its derivates in theMaillard reactionrdquoAminoAcids vol 32 no 2 pp 291ndash293 2007

[34] S Kuntz S Rudloff J Ehl R G Bretzel and C KunzldquoFood derived carbonyl compounds affect basal and stimulatedsecretion of interleukin-6 and -8 in Caco-2 cellsrdquo EuropeanJournal of Nutrition vol 48 no 8 pp 499ndash503 2009

[35] J P Casazza M E Felver and R L Veech ldquoThe metabolism ofacetone in ratrdquoThe Journal of Biological Chemistry vol 259 no1 pp 231ndash236 1984

[36] R A Cooper ldquoMetabolism of methylglyoxal in microorgan-ismsrdquo Annual Review of Microbiology vol 38 pp 49ndash68 1984

[37] K Fujioka and T Shibamoto ldquoDetermination of toxic carbonylcompounds in cigarette smokerdquo Environmental Toxicology vol21 no 1 pp 47ndash54 2006

[38] V Camel and A Bermond ldquoThe use of ozone and associ-ated oxidation processes in drinking water treatmentrdquo WaterResearch vol 32 no 11 pp 3208ndash3222 1998

[39] T-M Fu D J Jacob F Wittrock J P Burrows M Vrekoussisand D K Henze ldquoGlobal budgets of atmospheric glyoxal andmethylglyoxal and implications for formation of secondaryorganic aerosolsrdquo Journal of Geophysical Research D vol 113 no15 Article ID D15303 2008

[40] M P Kalapos ldquoMethylglyoxal in living organismsmdashchemistrybiochemistry toxicology and biological implicationsrdquo Toxicol-ogy Letters vol 110 no 3 pp 145ndash175 1999

[41] P J Beisswenger S K Howell R G Nelson M Mauerand B S Szwergold ldquo120572-oxoaldehyde metabolism and diabeticcomplicationsrdquo Biochemical Society Transactions vol 31 part 6pp 1358ndash1363 2003

[42] M P Kalapos ldquoMethylglyoxal and glucose metabolism ahistorical perspective and future avenues for researchrdquo DrugMetabolism and Drug Interactions vol 23 no 1-2 pp 69ndash912008

[43] M P Kalapos ldquoThe tandem of free radicals and methylglyoxalrdquoChemico-Biological Interactions vol 171 no 3 pp 251ndash2712008

[44] Q Cui and M Karplus ldquoCatalysis and specificity in enzymesa study of triosephosphate isomerase and comparison withmethyl glyoxal synthaserdquoAdvances in ProteinChemistry vol 66pp 315ndash372 2003

[45] J P Richard ldquoMechanism for the formation of methylglyoxalfrom triosephosphatesrdquo Biochemical Society Transactions vol21 no 2 pp 549ndash553 1993

[46] R A Cooper ldquo[104] Methylglyoxal synthaserdquo Methods inEnzymology vol 41 pp 502ndash508 1975


[47] A Dhar K Desai M Kazachmov P Yu and LWu ldquoMethylgly-oxal production in vascular smooth muscle cells from differentmetabolic precursorsrdquo Metabolism Clinical and Experimentalvol 57 no 9 pp 1211ndash1220 2008

[48] F Y Bondoc Z Bao W-Y Hu et al ldquoAcetone catabolismby cytochrome P450 2E1 studies with CYP2E1-null micerdquoBiochemical Pharmacology vol 58 no 3 pp 461ndash463 1999

[49] Z Turk I Nemet L Varga-Defteardarovic and N Car ldquoEle-vated level of methylglyoxal during diabetic ketoacidosis andits recovery phaserdquo Diabetes and Metabolism vol 32 no 2 pp176ndash180 2006

[50] J-Y Jung H S Yun J Lee and M-K Oh ldquoProduction of 12-propanediol from glycerol in saccharomyces cerevisiaerdquo Journalof Microbiology and Biotechnology vol 21 no 8 pp 846ndash8532011

[51] T Shibamoto ldquoAnalytical methods for trace levels of reactivecarbonyl compounds formed in lipid peroxidation systemsrdquoJournal of Pharmaceutical and Biomedical Analysis vol 41 no1 pp 12ndash25 2006

[52] H Esterbauer K H Cheeseman and M U Dianzani ldquoSepa-ration and characterization of the aldehydic products of lipidperoxidation stimulated by ADP-Fe2+ in rat liver microsomesrdquoThe Biochemical Journal vol 208 no 1 pp 129ndash140 1982

[53] P J Thornalley ldquoThe glyoxalase system in health and diseaserdquoMolecular Aspects of Medicine vol 14 no 4 pp 287ndash371 1993

[54] G A Lyles and J Chalmers ldquoThe metabolism of aminoacetoneto methylglyoxal by semicarbazide-sensitive amine oxidase inhuman umbilical arteryrdquoBiochemical Pharmacology vol 43 no7 pp 1409ndash1414 1992

[55] E J H Bechara F Dutra V E S Cardoso et al ldquoThe dualface of endogenous 120572-aminoketones pro-oxidizing metabolicweaponsrdquo Comparative Biochemistry and Physiology C vol 146no 1-2 pp 88ndash110 2007

[56] B A Callingham A E Crosbie and B A Rous ldquoSome aspectsof the pathophysiology of semicarbazide-sensitive amine oxi-dase enzymesrdquo Progress in Brain Research vol 106 pp 305ndash3211995

[57] G A Lyles ldquoMammalian plasma and tissue-bound semicar-bazide-sensitive amine oxidases biochemical pharmacologicaland toxicological aspectsrdquo International Journal of Biochemistryand Cell Biology vol 28 no 3 pp 259ndash274 1996

[58] P J Thornalley ldquoProtein and nucleotide damage by glyoxalandmethylglyoxal in physiological systemsmdashrole in ageing anddiseaserdquoDrugMetabolism andDrug Interactions vol 23 no 1-2pp 125ndash150 2008

[59] P J Thornalley A Langborg and H S Minhas ldquoFormation ofglyoxal methylglyoxal and 8-deoxyglucosone in the glycationof proteins by glucoserdquo The Biochemical Journal vol 344 part1 pp 109ndash116 1999

[60] P J Thornalley S Battah N Ahmed et al ldquoQuantitativescreening of advanced glycation endproducts in cellular andextracellular proteins by tandem mass spectrometryrdquo The Bio-chemical Journal vol 375 part 3 pp 581ndash592 2003

[61] N Ahmed P JThornalley J Dawczynski et al ldquoMethylglyoxal-derived hydroimidazolone advanced glycation end-products ofhuman lens proteinsrdquo Investigative Ophthalmology and VisualScience vol 44 no 12 pp 5287ndash5292 2003

[62] T Oya N Hattori Y Mizuno et al ldquoMethylglyoxal modi-fication of protein Chemical and immunochemical charac-terization of methylglyoxal-arginine adductsrdquo The Journal ofBiological Chemistry vol 274 no 26 pp 18492ndash18502 1999

[63] I N Shipanova M A Glomb and R H Nagaraj ldquoProteinmodification by methylglyoxal chemical nature and syntheticmechanism of amajor fluorescent adductrdquoArchives of Biochem-istry and Biophysics vol 344 no 1 pp 29ndash36 1997

[64] E B Frye T PDegenhardt S RThorpe and JW Baynes ldquoRoleof the Maillard reaction in aging of tissue proteins advancedglycation end product-dependent increase in imidazoliumcross-links in human lens proteinsrdquo The Journal of BiologicalChemistry vol 273 no 30 pp 18714ndash18719 1998

[65] KMBiemeDAlexander Fried andMO Lederer ldquoIdentifica-tion and quantification of major maillard cross-links in humanserum albumin and lens protein evidence for glucosepane asthe dominant compoundrdquo The Journal of Biological Chemistryvol 277 no 28 pp 24907ndash24915 2002

[66] T W C Lo M E Westwood A C McLellan T Selwoodand P J Thornalley ldquoBinding and modification of proteins bymethylglyoxal under physiological conditions a kinetic andmechanistic study with N120572-acetylarginine N120572- acetylcysteineand N120572-acetyllysine and bovine serum albuminrdquo The Journalof Biological Chemistry vol 269 no 51 pp 32299ndash32305 1994

[67] N Ahmed D Dobler M Dean and P J Thornalley ldquoPeptidemapping identifies hotspot site ofmodification in human serumalbumin by methylglyoxal involved in ligand binding andesterase activityrdquo The Journal of Biological Chemistry vol 280no 7 pp 5724ndash5732 2005

[68] E Kaufmann BO Boehm SD Sussmuth et al ldquoThe advancedglycation end-product N120576-(carboxymethyl)lysine level is ele-vated in cerebrospinal fluid of patients with amyotrophic lateralsclerosisrdquo Neuroscience Letters vol 371 no 2-3 pp 226ndash2292004

[69] L Southern J Williams and M M Esiri ldquoImmunohistochem-ical study of N-epsilon-carboxymethyl lysine (CML) in humanbrain relation to vascular dementiardquo BMC Neurology vol 7article 35 2007

[70] M Krautwald and G Munch ldquoAdvanced glycation end prod-ucts as biomarkers and gerontotoxinsmdasha basis to exploremethylglyoxal-lowering agents for Alzheimerrsquos diseaserdquo Exper-imental Gerontology vol 45 no 10 pp 744ndash751 2010

[71] T Jono T Kimura J Takamatsu et al ldquoAccumulation ofimidazolone pentosidine and N120576-(carboxymethyl)lysine inhippocampal CA4 pyramidal neurons of aged human brainrdquoPathology International vol 52 no 9 pp 563ndash571 2002

[72] N Ahmed U Ahmed P J Thornalley K Hager G Fleischerand G Munch ldquoProtein glycation oxidation and nitrationadduct residues and free adducts of cerebrospinal fluid inAlzheimerrsquos disease and link to cognitive impairmentrdquo Journalof Neurochemistry vol 92 no 2 pp 255ndash263 2005

[73] N Taniguchi M Takahashi H Sakiyama et al ldquoA commonpathway for intracellular reactive oxygen species productionby glycoxidative and nitroxidative stress in vascular endothelialcells and smoothmuscle cellsrdquoAnnals of the New York Academyof Sciences vol 1043 pp 521ndash528 2005

[74] K M Desai and L Wu ldquoFree radical generation by methylgly-oxal in tissuesrdquoDrug Metabolism and Drug Interactions vol 23no 1-2 pp 151ndash173 2008

[75] L F Dmitriev and V N Titov ldquoLipid peroxidation in relationto ageing and the role of endogenous aldehydes in diabetes andother age-related diseasesrdquo Ageing Research Reviews vol 9 no2 pp 200ndash210 2010

[76] T Chang and L Wu ldquoMethylglyoxal oxidative stress andhypertensionrdquo Canadian Journal of Physiology and Pharmacol-ogy vol 84 no 12 pp 1229ndash1238 2006


[77] I Dhar and K Desai ldquoChapter 30 Aging drugs to eliminatemethylglyoxal a reactive glucose metabolite and advancedglycation endproductsrdquo in Pharmacology L Gallelli Ed 2012

[78] M PKalapos KMDesai andLWu ldquoMethylglyoxal oxidativestress and agingrdquo inAging andAge-RelatedDisorders OxidativeStress in Applied Basic Research and Clinical Practice pp 149ndash167 Humana Press 2010

[79] X Huang F Wang W Chen Y Chen N Wang and Kvon Maltzan ldquoPossible link between the cognitive dysfunctionassociated with diabetes mellitus and the neurotoxicity ofmethylglyoxalrdquo Brain Research vol 1469 pp 82ndash91 2012

[80] A Szent-Gyorgyi Bioelectronics A Study in cellular regulationsDefense and cancer Academic Press NewYork NY USA 1968

[81] H Kon and A Szent Gyorgyi ldquoCharge transfer between amineand carbonylrdquo Proceedings of the National Academy of Sciencesof the United States of America vol 70 no 11 pp 3139ndash31401973

[82] M P Kalapos A Littauer and H De Groot ldquoHas reactiveoxygen a role in methylglyoxal toxicity A study on cultured rathepatocytesrdquo Archives of Toxicology vol 67 no 5 pp 369ndash3721993

[83] P H Yu S Wright E H Fan Z-R Lun and D Gubisne-Harberle ldquoPhysiological and pathological implications ofsemicarbazide-sensitive amine oxidaserdquo Biochimica et Biophys-ica Acta vol 1647 no 1-2 pp 193ndash199 2003

[84] J M Johnson H B Halsall and W R Heineman ldquoRedox acti-vation of galactose oxidase thin-layer electrochemical studyrdquoBiochemistry vol 24 no 7 pp 1579ndash1585 1985

[85] P J Kersten and T K Kirk ldquoInvolvement of a new enzymeglyoxal oxidase in extracellular H

2O2production by phane-

rochaete chrysosporiumrdquo Journal of Bacteriology vol 169 no5 pp 2195ndash2201 1987

[86] B Leuthner C Aichinger E Oehmen et al ldquoA H2O2-

producing glyoxal oxidase is required for filamentous growthand pathogenicity in Ustilago maydisrdquo Molecular Genetics andGenomics vol 272 no 6 pp 639ndash650 2005

[87] Y Hiraku J Sugimoto T Yamaguchi and S KawanishildquoOxidative DNA damage induced by aminoacetone an aminoacid metaboliterdquo Archives of Biochemistry and Biophysics vol365 no 1 pp 62ndash70 1999

[88] F Dutra F S Knudsen D Curi and E J H Bechara ldquoAerobicoxidation of aminoacetone a threonine catabolite iron catalysisand coupled iron release from ferritinrdquo Chemical Research inToxicology vol 14 no 9 pp 1323ndash1329 2001

[89] C C C Vidigal and G Cilento ldquoEvidence for the generation ofexcited methylglyoxal in the myoglobin catalyzed oxidation ofacetoacetaterdquo Biochemical and Biophysical Research Communi-cations vol 62 no 2 pp 184ndash190 1975

[90] K Takayama M Nakano and K Zinner ldquoGeneration ofelectronic energy in the myoglobin catalyzed oxidation ofacetoacetate to methylglyoxalrdquo Archives of Biochemistry andBiophysics vol 176 no 2 pp 663ndash670 1976

[91] T Yamaguchi and K Nakagawa ldquoMutagenicity of and for-mation of oxygen radicals by trioses and glyoxal derivativesrdquoAgricultural and Biological Chemistry vol 47 no 11 pp 2461ndash2465 1983

[92] P Thornalley S Wolff J Crabbe and A Stern ldquoThe autox-idation of glyceraldehyde and other simple monosaccha-rides under physiological conditions catalysed by buffer ionsrdquoBiochimica et Biophysica Acta vol 797 no 2 pp 276ndash287 1984

[93] P J Thornalley S P Wolff M J Crabbe and A Stern ldquoTheoxidation of oxyhaemoglobin by glyceraldehyde and othersimple monosaccharidesrdquoThe Biochemical Journal vol 217 no3 pp 615ndash622 1984

[94] R Atkinson W P L Carter K R Darnall M Winer andJ N Pitts ldquoA smog chamber and modeling study of the gasphase NOxmdashair photooxidation of toluene and the cresolsrdquoInternational Journal of Chemical Kinetics vol 12 no 11 pp779ndash836 1980

[95] H Nukaya Y Inaoka H Ishida et al ldquoModification of theamino group of guanosine by methylglyoxal and other 120572-ketoaldehydes in the presence of hydrogen peroxiderdquo Chemicaland Pharmaceutical Bulletin vol 41 no 4 pp 649ndash653 1993

[96] C Angeloni S Turroni L Bianchi et al ldquoNovel targets of sul-foraphane in primary cardiomyocytes identified by proteomicanalysisrdquo PLoS ONE vol 8 no 12 Article ID e83283 2013

[97] T Chang R Wang and L Wu ldquoMethylglyoxal-induced nitricoxide and peroxynitrite production in vascular smooth musclecellsrdquo Free Radical Biology and Medicine vol 38 no 2 pp 286ndash293 2005

[98] C Ho P-H Lee W-J Huang Y-C Hsu C-L Lin and J-Y Wang ldquoMethylglyoxal-induced fibronectin gene expressionthrough ras-mediated NADPH oxidase activation in renalmesangial cellsrdquo Nephrology vol 12 no 4 pp 348ndash356 2007

[99] R A Ward and K R McLeish ldquoMethylglyoxal a stimulus toneutrophil oxygen radical production in chronic renal failurerdquoNephrology Dialysis Transplantation vol 19 no 7 pp 1702ndash17072004

[100] J Nicolay J Schneider O Niemoeller et al ldquoStimulation of sui-cidal erythrocyte death by methylglyoxalrdquo Cellular Physiologyand Biochemistry vol 18 no 4-5 pp 223ndash232 2006

[101] Y S Park Y H Koh M Takahashi et al ldquoIdentification ofthe binding site of methylglyoxal on gluthathione peroxidasemethylglyoxal inhibits glutathione peroxidase activity via bind-ing to glutathione binding sites Arg 184 and 185rdquo Free RadicalResearch vol 37 no 2 pp 205ndash211 2003

[102] P J Thornalley ldquoGlutathione-dependent detoxification of 120572-oxoaldehydes by the glyoxalase system Involvement in dis-ease mechanisms and antiproliferative activity of glyoxalase IinhibitorsrdquoChemico-Biological Interactions vol 111-112 pp 137ndash151 1998

[103] J H Kang ldquoModification and inactivation of human CuZn-superoxide dismutase by methylglyoxalrdquo Molecules and Cellsvol 15 no 2 pp 194ndash199 2003

[104] N Rabbani and P J Thornalley ldquoDicarbonyls linked to damagein the powerhouse glycation of mitochondrial proteins andoxidative stressrdquoBiochemical Society Transactions vol 36 part5pp 1045ndash1050 2008

[105] M G Rosca T G Mustata M T Kinter et al ldquoGlycation ofmitochondrial proteins from diabetic rat kidney is associatedwith excess superoxide formationrdquo The American Journal ofPhysiology Renal Physiology vol 289 no 2 pp F420ndashF4302005

[106] J Du H Suzuki F Nagase et al ldquoSuperoxide-mediated earlyoxidation and activation of ASK1 are important for initiatingmethylglyoxal-induced apoptosis processrdquo Free Radical Biologyand Medicine vol 31 no 4 pp 469ndash478 2001

[107] G Basta G Lazzerini M Massaro et al ldquoAdvanced gly-cation end products activate endothelium through signal-transduction receptor RAGE a mechanism for amplification ofinflammatory responsesrdquo Circulation vol 105 no 7 pp 816ndash822 2002


[108] J Chen S V Brodsky D M Goligorsky et al ldquoGlycated colla-gen I induces premature senescence-like phenotypic changes inendothelial cellsrdquo Circulation Research vol 90 no 12 pp 1290ndash1298 2002

[109] S Kikuchi K Shinpo M Takeuchi et al ldquoGlycationmdasha sweettempter for neuronal deathrdquo Brain Research Reviews vol 41 no2-3 pp 306ndash323 2003

[110] M-P Wautier O Chappey S Corda D M Stern A MSchmidt and J-L Wautier ldquoActivation of NADPH oxidaseby AGE links oxidant stress to altered gene expression viaRAGErdquoThe American Journal of Physiology Endocrinology andMetabolism vol 280 no 5 pp E685ndashE694 2001

[111] M E Westwood and P J Thornalley ldquoInduction of synthesisand secretion of interleukin 1120573 in the human monocytic THP-1 cells by human serum albumins modified with methylglyoxaland advanced glycation endproductsrdquo Immunology Letters vol50 no 1-2 pp 17ndash21 1996

[112] P J Thornalley ldquoCell activation by glycated proteins AGEreceptors receptor recognition factors and functional classifi-cation of AGEsrdquo Cellular and Molecular Biology vol 44 no 7pp 1013ndash1023 1998

[113] A Bierhaus S Chevion M Chevion et al ldquoAdvanced glycationend product-induced activation of NF-120581B is suppressed by 120572-lipoic acid in cultured endothelial cellsrdquoDiabetes vol 46 no 9pp 1481ndash1490 1997

[114] M P Vitek K Bhattacharya J M Glendening et al ldquoAdvancedglycation end products contribute to amyloidosis in Alzheimerdiseaserdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 91 no 11 pp 4766ndash4770 1994

[115] T Kimura J Takamatsu N Araki et al ldquoAre advanced glyca-tion end-products associated with amyloidosis in Alzheimerrsquosdiseaserdquo NeuroReport vol 6 no 6 pp 866ndash868 1995

[116] S-Y Ko Y-P Lin Y-S Lin and S-S Chang ldquoAdvancedglycation end products enhance amyloid precursor proteinexpression by inducing reactive oxygen speciesrdquo Free RadicalBiology and Medicine vol 49 no 3 pp 474ndash480 2010

[117] X H Li L L Du X S Cheng et al ldquoGlycation exacerbates theneuronal toxicity of beta-amyloidrdquo Cell Death and Disease vol4 article e673 2013

[118] H M Schipper ldquoApolipoprotein E implications for AD neu-robiology epidemiology and risk assessmentrdquo Neurobiology ofAging vol 32 no 5 pp 778ndash790 2011

[119] G Bu ldquoApolipoprotein e and its receptors in Alzheimerrsquosdisease pathways pathogenesis and therapyrdquo Nature ReviewsNeuroscience vol 10 no 5 pp 333ndash344 2009

[120] Y Namba M Tomonaga H Kawasaki E Otomo and KIkeda ldquoApolipoprotein E immunoreactivity in cerebral amyloiddeposits and neurofibrillary tangles in Alzheimerrsquos diseaseand kuru plaque amyloid in Creutzfeldt-Jakob diseaserdquo BrainResearch vol 541 no 1 pp 163ndash166 1991

[121] E Kok S Haikonen T Luoto et al ldquoApolipoprotein E-dependent accumulation of alzheimer disease-related lesionsbegins in middle agerdquo Annals of Neurology vol 65 no 6 pp650ndash657 2009

[122] T Polvikoski R Sulkava M Haltia et al ldquoApolipoprotein Edementia and cortical deposition of 120573-amyloid proteinrdquo TheNew England Journal of Medicine vol 333 no 19 pp 1242ndash12471995

[123] Y M Li and D W Dickson ldquoEnhanced binding of advancedglycation endproducts (AGE) by the ApoE4 isoform linksthe mechanism of plaque deposition in Alzheimerrsquos diseaserdquoNeuroscience Letters vol 226 no 3 pp 155ndash158 1997

[124] G Munch BWestcott T Menini and A Gugliucci ldquoAdvancedglycation endproducts and their pathogenic roles in neurologi-cal disordersrdquo Amino Acids vol 42 no 4 pp 1221ndash1236 2012

[125] J J Li M Surini S Catsicas E Kawashima and C BourasldquoAge-dependent accumulation of advanced glycosylation endproducts in human neuronsrdquoNeurobiology of Aging vol 16 no1 pp 69ndash76 1995

[126] A Wong H-J Luth W Deuther-Conrad et al ldquoAdvancedglycation endproducts co-localize with inducible nitric oxidesynthase in Alzheimerrsquos diseaserdquo Brain Research vol 920 no1-2 pp 32ndash40 2001

[127] V Prakash Reddy M E Obrenovich C S Atwood G Perryand M A Smith ldquoInvolvement of Maillard reactions inAlzheimer diseaserdquoNeurotoxicity Research vol 4 no 3 pp 191ndash209 2002

[128] M A Smith S Taneda P L Richey et al ldquoAdvanced Maillardreaction end products are associated with Alzheimer diseasepathologyrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 12 pp 5710ndash5714 1994

[129] V V Shuvaev I Laffont J-M Serot J Fujii N Taniguchi andG Siest ldquoIncreased protein glycation in cerebrospinal fluid ofAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 22 no 3 pp397ndash402 2001

[130] K J Bar S Franke B Wenda et al ldquoPentosidine and N120576-(carboxymethyl)-lysine in Alzheimerrsquos disease and vasculardementiardquo Neurobiology of Aging vol 24 no 2 pp 333ndash3382003

[131] L Mucke ldquoNeuroscience Alzheimerrsquos diseaserdquoNature vol 461no 7266 pp 895ndash897 2009

[132] M S Beeri E Moshier J Schmeidler et al ldquoSerum concentra-tion of an inflammatory glycotoxinmethylglyoxal is associatedwith increased cognitive decline in elderly individualsrdquoMecha-nisms of Ageing andDevelopment vol 132 no 11-12 pp 583ndash5872011

[133] M A Lovell C Xie and W R Markesbery ldquoAcrolein isincreased in Alzheimerrsquos disease brain and is toxic to primaryhippocampal culturesrdquo Neurobiology of Aging vol 22 no 2 pp187ndash194 2001

[134] J K Andersen ldquoOxidative stress in neurodegeneration cause orconsequencerdquo Nature Medicine vol 5 pp S18ndashS25 2004

[135] A Nunomura G Perry G Aliev et al ldquoOxidative damage is theearliest event in Alzheimer diseaserdquo Journal of Neuropathologyand Experimental Neurology vol 60 no 8 pp 759ndash767 2001

[136] R H Swerdlow ldquoBrain aging Alzheimerrsquos disease and mito-chondriardquo Biochimica et Biophysica Acta vol 1812 no 12 pp1630ndash1639 2011

[137] P F Good P Werner A Hsu C W Olanow and D PPerl ldquoEvidence for neuronal oxidative damage in Alzheimerrsquosdiseaserdquo The American Journal of Pathology vol 149 no 1 pp21ndash28 1996

[138] S G de Arriba G Stuchbury J Yarin J Burnell C Loskeand G Munch ldquoMethylglyoxal impairs glucose metabolismand leads to energy depletion in neuronal cells-protection bycarbonyl scavengersrdquo Neurobiology of Aging vol 28 no 7 pp1044ndash1050 2007

[139] S-M Huang H-C Chuang C-H Wu and G-C Yen ldquoCyto-protective effects of phenolic acids on methylglyoxal-inducedapoptosis in Neuro-2A cellsrdquo Molecular Nutrition and FoodResearch vol 52 no 8 pp 940ndash949 2008

[140] Y-J Chen X-B Huang Z-X Li L-L Yin W-Q Chenand L Li ldquoTenuigenin protects cultured hippocampal neurons


against methylglyoxal-induced neurotoxicityrdquo European Jour-nal of Pharmacology vol 645 no 1ndash3 pp 1ndash8 2010

[141] Q Q Yin C F Dong S Q Dong et al ldquoAGEs induce celldeath via oxidative and endoplasmic reticulum stresses in bothhuman SH-SY5Y neuroblastoma cells and rat cortical neuronsrdquoCellular and Molecular Neurobiology vol 32 no 8 pp 1299ndash1309 2012

[142] F Liu Z Liang and C X Gong ldquoHyperphosphorylation of tauand protein phosphatases in Alzheimer diseaserdquo PanminervaMedica vol 48 no 2 pp 97ndash108 2006

[143] K Iqbal F Liu C-X Gong A C del Alonso and I Grundke-Iqbal ldquoMechanisms of tau-induced neurodegenerationrdquo ActaNeuropathologica vol 118 no 1 pp 53ndash69 2009

[144] E Planel T Miyasaka T Launey et al ldquoAlterations in glucosemetabolism induce hypothermia leading to tau hyperphospho-rylation through differential inhibition of kinase and phos-phatase activities implications for Alzheimerrsquos diseaserdquo Journalof Neuroscience vol 24 no 10 pp 2401ndash2411 2004

[145] M Hu J F Waring M Gopalakrishnan and J Li ldquoRole ofGSK-3120573 activation and 1205727 nAChRs in A120573 1-42-induced tauphosphorylation in PC12 cellsrdquo Journal of Neurochemistry vol106 no 3 pp 1371ndash1377 2008

[146] C X Gong ldquoDephosphorylation of Alzheimerrsquos disease abnor-mally phosphorylated tau by protein phosphatase-2Ardquo Neuro-science vol 61 no 4 pp 765ndash772 1994

[147] J-ZWang C-XGong T Zaidi I Grundke-Iqbal andK IqballdquoDephosphorylation of Alzheimer paired helical filaments byprotein phosphatase-2A and -2Brdquo The Journal of BiologicalChemistry vol 270 no 9 pp 4854ndash4860 1995

[148] X H Li J Z Xie X Jiang et al ldquoMethylglyoxal inducestau hyperphosphorylation via promoting AGEs formationrdquoNeuroMolecular Medicine vol 14 no 4 pp 338ndash348 2012

[149] M A Smith M Rudnicka-Nawrot P L Richey et alldquoCarbonyl-related posttranslational modification of neurofila-ment protein in the neurofibrillary pathology of Alzheimerrsquosdiseaserdquo Journal of Neurochemistry vol 64 no 6 pp 2660ndash2666 1995

[150] P Cras M A Smith P L Richey S L Siedlak P Mulvihill andG Perry ldquoExtracellular neurofibrillary tangles reflect neuronalloss and provide further evidence of extensive protein crosslinking in Alzheimer diseaserdquo Acta Neuropathologica vol 89no 4 pp 291ndash295 1995

[151] B Kuhla C Haase K Flach H J Luth T Arendt and GMunch ldquoEffect of pseudophosphorylation and cross-linkingby lipid peroxidation and advanced glycation end productprecursors on tau aggregation and filament formationrdquo J BiolChem vol 282 no 10 pp 6984ndash6991 2007

[152] M T Lin and M F Beal ldquoMitochondrial dysfunction andoxidative stress in neurodegenerative diseasesrdquoNature vol 443no 7113 pp 787ndash795 2006

[153] D Pratico ldquoOxidative stress hypothesis in Alzheimerrsquos diseasea reappraisalrdquoTrends in Pharmacological Sciences vol 29 no 12pp 609ndash615 2008

[154] X Zhu H-G Lee A K Raina G Perry and M A SmithldquoThe role of mitogen-activated protein kinase pathways inAlzheimerrsquos diseaserdquo NeuroSignals vol 11 no 5 pp 270ndash2812002

[155] A Chiarini I Dal Pra M Marconi B Chakravarthy J FWhitfield andUArmato ldquoCalcium-sensing receptor (CaSR) inhuman brainrsquos pathophysiology Roles in late-onset Alzheimerrsquosdisease (LOAD)rdquoCurrent Pharmaceutical Biotechnology vol 10no 3 pp 317ndash326 2009

[156] Y Hashimoto O Tsuji T Niikura et al ldquoInvolvement of c-Jun N-terminal kinase in amyloid precursor protein-mediatedneuronal cell deathrdquo Journal of Neurochemistry vol 84 no 4pp 864ndash877 2003

[157] C A Marques U Keil A Bonert et al ldquoNeurotoxic mecha-nisms caused by the alzheimerrsquos disease-linked Swedish amyloidprecursor protein Mutation oxidative stress caspases and theJNK pathwayrdquoThe Journal of Biological Chemistry vol 278 no30 pp 28294ndash28302 2003

[158] B Puig T Gomez-Isla E Ribe et al ldquoExpression of stress-activated kinases c-Jun N-terminal kinase (SAPKJNK-P) andp38 kinase (p38-P) and tau hyperphosphorylation in neuritessurrounding 120573A plaques in APP Tg2576 micerdquoNeuropathologyand Applied Neurobiology vol 30 no 5 pp 491ndash502 2004

[159] E Tamagno M Parola P Bardini et al ldquo120573-site APP cleavingenzyme up-regulation induced by 4-hydroxynonenal is medi-ated by stress-activated protein kinases pathwaysrdquo Journal ofNeurochemistry vol 92 no 3 pp 628ndash636 2005

[160] C Shen Y Chen H Liu et al ldquoHydrogen peroxide pro-motes A120573 production through JNK-dependent activation of 120574-secretaserdquo The Journal of Biological Chemistry vol 283 no 25pp 17721ndash17730 2008

[161] A Colombo A Bastone C Ploia et al ldquoJNK regulates APPcleavage and degradation in a model of Alzheimerrsquos diseaserdquoNeurobiology of Disease vol 33 no 3 pp 518ndash525 2009

[162] Z Muresan and V Muresan ldquoThe amyloid-120573 precursor proteinis phosphorylated via distinct pathways during differentiationmitosis stress and degenerationrdquoMolecular Biology of the Cellvol 18 no 10 pp 3835ndash3844 2007

[163] X Fan R Subramaniam M F Weiss and V M MonnierldquoMethylglyoxal-bovine serum albumin stimulates tumor necro-sis factor alpha secretion in RAW 2647 cells through activationof mitogen-activating protein kinase nuclear factor 120581B andintracellular reactive oxygen species formationrdquo Archives ofBiochemistry and Biophysics vol 409 no 2 pp 274ndash286 2003

[164] A Pal I Bhattacharya K Bhattacharya C Mandal andM Ray ldquoMethylglyoxal induced activation of murine peri-toneal macrophages and surface markers of T lymphocytes inSarcoma-180 bearingmice Involvement ofMAP kinase NF-120581120573signal transduction pathwayrdquo Molecular Immunology vol 46no 10 pp 2039ndash2044 2009

[165] S-M Huang C-L Hsu H-C Chuang P-H Shih C-HWu and G-C Yen ldquoInhibitory effect of vanillic acid onmethylglyoxal-mediated glycation in apoptoticNeuro-2A cellsrdquoNeuroToxicology vol 29 no 6 pp 1016ndash1022 2008

[166] L Heimfarth S O Loureiro P Pierozan et al ldquoMethylglyoxal-induced cytotoxicity in neonatal rat brain a role for oxidativestress andMAP kinasesrdquoMetabolic Brain Disease vol 28 no 3pp 429ndash438 2013

[167] PMatafome C Sena and R Seica ldquoMethylglyoxal obesity anddiabetesrdquo Endocrine vol 43 no 3 pp 472ndash484 2013

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


TauTau

Vascularabnormality

Amyloidplaque

ApoE4

A120573

A120573-degradingenzyme

Microglial cell

Oligomers

Impairedsynapse

Neurofibrillarytangles

Figure 1 Classical processes participating in the etiology and pathogenesis of AD (modified from [131])

[12] In AD AGEs accumulate in neurons and astroglia andare also found associated with neuritic amyloid plaques andNFTs [13ndash16] MGmay also contribute to neurodegenerationtriggering oxidative stress [17ndash19] Oxidative stress is char-acterized by an imbalance between reactive oxygen species(ROS) production and the detoxifying endogenous systemThere is accumulating evidence suggesting a key role ofoxidative stress in the pathophysiology of AD [20ndash23] Acentral role for oxidative stress by the activation of NADPHoxidase in astrocytes has been demonstrated as the causeof A120573-induced neuronal death [24] and of alterations inastrocyte mitochondrial bioenergetics that may in turn affectneuronal functioning andor survival [25]

As oxidative stress and MG are closely interlinked therole ofMG andMG-induced production of AGEs and ROS inthe development of AD is reviewed in this paper In additionthe ability of MG to modulate detrimental redox signaling inAD has been considered

2 Methylglyoxal Production

MG is a reactive intermediate of cellular metabolism presentubiquitously in all cells It is produced under both normaland pathological conditions via several different pathwaysinvolving both enzymatic and nonenzymatic reactions [26]The rate of MG formation depends on the organism tissuecell metabolism and physiological conditions therefore MGplasma concentration reflects these factors Plasmatic MGcan be derived from exogenous sources such as coffeealcoholic beverages and food [27 28] and from endogenoussources in situ formation in the plasma release from cellsand loss from injured cells [29]

Since MG is ubiquitously present in living cells almostall foods and beverages contain MG as reviewed by Vistoli etal [30] The main sources of MG are represented by mono-

oligo- and polysaccharides and lipids [31] Several reactionsand processes are involved in the accumulation of MGautoxidation photodegradation and heating and prolongedstorage are the main sources of MG as a degradation productin foodstuff [32ndash35] Moreover many microorganisms pro-duce and release MG fermentation can be a critical processincreasingMG levels in alcoholic drinks and fermented foods[36] MG is reported to originate also from environmentalsources Cigarette smoke is one of the combustion processesthat can generate MG [37] drinking water can contain MGdue to the purification treatments [38] rainwater can absorbMG from polluted air and transmits it to the soil [39]

Endogenously derived MG is formed during carbohy-drate and lipid and amino acid metabolisms and involvesboth enzymatic and nonenzymatic reactions [40ndash43] Theenzymes that catalyze the reactions of MG synthesis areMG synthase cytochrome P450 2E1 myeloperoxidase andamino oxidase participating in glycolytic bypass ace-tone metabolism and amino acid breakdown respectivelynonenzymatic pathways include the spontaneous decompo-sition of dihydroxyacetone phosphate the Maillard reactionthe oxidation of acetol and lipid peroxidation [42]

The main pathway leading to MG is linked to carbohy-drate metabolism and involves enzymatic and nonenzymaticdegradation of the triosephosphate intermediates glyceralde-hyde 3-phosphate and dihydroxyacetone-phosphate deriv-ing from glycolysis [40 44 45] It should be noted thattriosephosphates originate not only from glycolytic processesbut also from other routes of glucose metabolism (Entner-Doudoroff pathway hexose monophosphate route) and fromxylitol metabolism or the activity of glycerophosphate dehy-drogenase linking glycerol breakdown to MG production[40] Dihydroxyacetone phosphate can be converted to MGby either spontaneous nonenzymatic elimination of thephosphate group or by the enzymatic contribution of MG








120576-(1-carbo-


































Oxidativestress

JNK ERK p38 MAPK

Apoptosis


MG

GSK-3120573 PP2

NFTs


AGEs

Glycated

Glycated

NFTs

APP

A120573-deposit

A120573-deposit

Astroglial cells

Microglial cells

Synapticproteins




8 Conclusions



Abbreviation List

























Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








120576-(1-carbo-


































Oxidativestress

JNK ERK p38 MAPK

Apoptosis


MG

GSK-3120573 PP2

NFTs


AGEs

Glycated

Glycated

NFTs

APP

A120573-deposit

A120573-deposit

Astroglial cells

Microglial cells

Synapticproteins




8 Conclusions



Abbreviation List

























Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology























Oxidativestress

JNK ERK p38 MAPK

Apoptosis


MG

GSK-3120573 PP2

NFTs


AGEs

Glycated

Glycated

NFTs

APP

A120573-deposit

A120573-deposit

Astroglial cells

Microglial cells

Synapticproteins




8 Conclusions



Abbreviation List

























Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






















Acknowledgments


References
























































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology











































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article role of methylglyoxal in alzheimer s...

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