Redox Signaling in Degenerative Diseases: From Molecular Mechanisms to Health ImplicationsView this Special Issue
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Cristina Angeloni, Laura Zambonin, Silvana Hrelia, "Role of Methylglyoxal in Alzheimer’s Disease", BioMed Research International, vol. 2014, Article ID 238485, 12 pages, 2014. https://doi.org/10.1155/2014/238485
Role of Methylglyoxal in Alzheimer’s Disease
Alzheimer’s disease is the most common and lethal neurodegenerative disorder. The major hallmarks of Alzheimer’s disease are extracellular aggregation of amyloid β peptides and, the presence of intracellular neurofibrillary tangles formed by precipitation/aggregation of hyperphosphorylated tau protein. The etiology of Alzheimer’s disease is multifactorial and a full understanding of its pathogenesis remains elusive. Some years ago, it has been suggested that glycation may contribute to both extensive protein cross-linking and oxidative stress in Alzheimer’s disease. Glycation is an endogenous process that leads to the production of a class of compounds known as advanced glycation end products (AGEs). Interestingly, increased levels of AGEs have been observed in brains of Alzheimer’s disease patients. Methylglyoxal, a reactive intermediate of cellular metabolism, is the most potent precursor of AGEs and is strictly correlated with an increase of oxidative stress in Alzheimer’s disease. Many studies are showing that methylglyoxal and methylglyoxal-derived AGEs play a key role in the etiopathogenesis of Alzheimer's disease.
Alzheimer’s disease (AD) is the most common and lethal neurodegenerative disorder characterized by progressive neuronal loss and neuroinflammation in the brain and associated with progressive cognitive decline, memory impairment, and changes in behavior and personality, with rising incidence among elderly people. One of the pathological hallmarks of AD is neuritic plaques in the cerebral cortex and hippocampus. Amyloid (A), a 40–42 amino-acid peptide generated by proteolytic cleavages of the amyloid- protein precursor (APP) , is one of the main components of neuritic plaques. A is cytotoxic and capable of inducing oxidative stress and neurodegeneration [2, 3]. Another distinctive feature of AD is neurofibrillary tangles (NFTs), composed of bundles of paired helical filaments (PHFs) , mainly containing hyperphosphorylated microtubule-associated tau protein (MAP-tau) . Under normal physiological conditions, tau promotes assembly and stability of microtubules and is thus involved in axonal transport [6, 7]. In AD, tau proteins aggregate forming fibrillar insoluble intracellular inclusions. The main processes involved in the etiology and pathogenesis of AD are reported in Figure 1.
The full understanding of the etiology and pathogenesis of AD has remained elusive, and more and more evidences are confirming that AD is a disease with numerous genetic and environmental contributing factors. Some years ago, it has been proposed that a chemical process known as glycation may contribute to both extensive protein cross-linking and oxidative stress in AD . Nonenzymatic protein glycation is an endogenous process in which reducing sugars react with amino groups in proteins through a series of Maillard reactions forming reversible Schiff base and Amadori compounds, producing a heterogeneous class of molecules, collectively termed advanced glycation end products (AGEs) . The -ketoaldehyde methylglyoxal (MG), formed endogenously as a by-product of the glycolytic pathway, by degradation of triosephosphates or nonenzymatically by sugar fragmentation reactions, is the most potent precursor of AGE formation . MG is able to induce cellular damage, cross-linking of proteins, and glycation  playing an important role in the pathogenesis of many neurodegenerative diseases . In AD, AGEs accumulate in neurons and astroglia and are also found associated with neuritic amyloid plaques and NFTs [13–16]. MG may also contribute to neurodegeneration triggering oxidative stress [17–19]. Oxidative stress is characterized by an imbalance between reactive oxygen species (ROS) production and the detoxifying endogenous system. There is accumulating evidence suggesting a key role of oxidative stress in the pathophysiology of AD [20–23]. A central role for oxidative stress by the activation of NADPH oxidase in astrocytes has been demonstrated as the cause of A-induced neuronal death  and of alterations in astrocyte mitochondrial bioenergetics that may in turn affect neuronal functioning and/or survival .
As oxidative stress and MG are closely interlinked, the role of MG and MG-induced production of AGEs and ROS in the development of AD is reviewed in this paper. In addition, the ability of MG to modulate detrimental redox signaling in AD has been considered.
2. Methylglyoxal Production
MG is a reactive intermediate of cellular metabolism, present ubiquitously in all cells. It is produced under both normal and pathological conditions via several different pathways, involving both enzymatic and nonenzymatic reactions . The rate of MG formation depends on the organism, tissue, cell metabolism, and physiological conditions; therefore, MG plasma concentration reflects these factors. Plasmatic MG can be derived from exogenous sources, such as coffee, alcoholic beverages, and food [27, 28] and from endogenous sources: in situ formation in the plasma, release from cells, and loss from injured cells .
Since MG is ubiquitously present in living cells, almost all foods and beverages contain MG, as reviewed by Vistoli et al. . The main sources of MG are represented by mono-, oligo-, and polysaccharides and lipids . Several reactions and processes are involved in the accumulation of MG: autoxidation, photodegradation, and heating and prolonged storage are the main sources of MG as a degradation product in foodstuff [32–35]. Moreover, many microorganisms produce and release MG: fermentation can be a critical process increasing MG levels in alcoholic drinks and fermented foods . MG is reported to originate also from environmental sources. Cigarette smoke is one of the combustion processes that can generate MG ; drinking water can contain MG due to the purification treatments ; rainwater can absorb MG from polluted air and transmits it to the soil .
Endogenously derived MG is formed during carbohydrate and lipid and amino acid metabolisms and involves both enzymatic and nonenzymatic reactions [40–43]. The enzymes that catalyze the reactions of MG synthesis are MG synthase, cytochrome P450 2E1, myeloperoxidase, and amino oxidase, participating in glycolytic bypass, acetone metabolism, and amino acid breakdown, respectively; nonenzymatic pathways include the spontaneous decomposition of dihydroxyacetone phosphate, the Maillard reaction, the oxidation of acetol, and lipid peroxidation .
The main pathway leading to MG is linked to carbohydrate metabolism and involves enzymatic and nonenzymatic degradation of the triosephosphate intermediates glyceraldehyde 3-phosphate and dihydroxyacetone-phosphate deriving from glycolysis [40, 44, 45]. It should be noted that triosephosphates originate not only from glycolytic processes but also from other routes of glucose metabolism (Entner-Doudoroff pathway, hexose monophosphate route) and from xylitol metabolism or the activity of glycerophosphate dehydrogenase, linking glycerol breakdown to MG production . Dihydroxyacetone phosphate can be converted to MG by either spontaneous nonenzymatic elimination of the phosphate group or by the enzymatic contribution of MG synthase, an enzyme found in prokaryotic and mammalian systems [36, 46]. MG can also derive via the Maillard reaction in vivo under physiological conditions, similar to what is observed during food cooking and through the glycation of macromolecules and the autoxidation of carbohydrates .
MG production deriving from lipid metabolism is mainly linked to the acetone metabolism . Acetone is derived from acetoacetate by myeloperoxidase activity and is converted to MG by the cytochrome P450 2E1 via acetol as intermediate . In pathological conditions like ketosis and diabetic ketoacidosis, the oxidation of ketone bodies is likely to be an important source of MG . In addition, triacylglycerol hydrolysis produces glycerol that can be transformed into MG through glycerolphosphate produced by a specific glycerol kinase . Lipoperoxidation is another nonenzymatic process leading to MG formation [51, 52].
The catabolism of the aminoacids threonine and glycine (and partially tyrosine) can also generate MG through the aminoacetone intermediate [53–55]. This metabolic oxidative pathway is mediated by the enzyme semicarbazide sensitive amine oxidase (SSAO) and appears to be exacerbated in low coenzyme A states [56, 57].
3. Methylglyoxal Induced AGE Production
MG is able to induce protein glycation leading to the formation of AGEs  and is believed to be the most important source of AGEs. Glycation of proteins is a complex series of parallel and sequential reactions known as Maillard reaction . Glycation starts with the reaction of glucose with lysine and leads to the formation of fructosyl-lysine (FL) and N-terminal amino acid residue-derived fructosamines while later stage reactions produce stable adducts . It has been observed that FL degrades slowly to form AGEs  while MG reacts relatively rapidly with proteins to form AGEs , in particular MG is up to 20,000 times more reactive than glucose in glycation reactions . MG reacts almost exclusively with arginine residues and to a lesser extent with lysine, cysteine, and tryptophan residues. The reaction of MG with arginine leads to the formation of cyclic imidazolone adducts (MG-H)  and other related structural isomers. MG-H is formed as three structural isomers: N-(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), and 2-amino-5-(2-amino-4-hydro-4-methyl-5-imidazolon-1-yl)pentanoic acid (MG-H3) . These adducts can undergo other reactions; they can add a second MG molecule yielding either N-(4-carboxy-4,6-dimethyl-5,6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-L-ornithine (THP)  or argpyrimidine (N-(5-hydroxy-4,6-dimethylpyrimidine-2-yl)-l-ornithine) . MG also reacts with lysine residues to form the -(1-carboxyethyl)-L-lysine (CEL) and -(1-carboxymethyl)-L-lysine (CML) adducts and the lysine dimer 1,3-di(-lysino)-4-methyl-imidazolium (MOLD) . With one lysine and one arginine residue, MG forms 2-ammonio-6-(2-[(4-ammonio-5-oxido-5-oxopentyl) amino]-4-methyl-4,5-dihydro-1H-imidazol-5-ylidene amino) hexanoate (MODIC) . MG can react also with cysteine residues giving reversible hemithioacetal adducts  and could spontaneously modify tryptophan residues yielding carboline derivatives .
In human serum albumin, the following concentrations of MG-derived AGEs were detected: MG-H1 2493 ± 87 mmol/mol protein; argpyrimidine 200 ± 40 mmol/mol protein; CEL 29.7 ± 1.8 mmol/mol protein; and MOL 5 ± 1 mmol/mol protein . In cerebrospinal fluid of patients with amyotrophic lateral sclerosis, elevated levels of CML were reported , and the tissue levels of CML in cortical neurons and cerebral vessels were related to the severity of cognitive impairment in patients with cerebrovascular disease . It has been demonstrated that MG is involved in the increased levels of AGEs observed in AD  and MG-derived AGEs such as CEL and MOLD and MG-derived hydroimidazolone have each been identified in intracellular protein deposits in neurofibrillary tangles  and cerebrospinal fluid .
4. Methylglyoxal Induced ROS Production
The production of ROS and reactive nitrogen species (RNS) during MG metabolism have been extensively depicted in some reviews [43, 73, 74] and a large body of literature describes the correlation among MG, AGEs, oxidative stress, and pathologies  such as diabetes , hypertension , aging [74, 77, 78], and neurodegeneration [13, 79].
Free radicals and/or ROS and RNS can be produced during both the formation of MG and its degradation; the reactions involved in these processes could be summarized as follows. The enzymatic formation of MG from aminoacetone (catalyzed by SSAO) or from acetol (catalyzed by galactose oxidase) is coupled to hydrogen peroxide production [83, 84]; hydrogen peroxide is produced also when MG is converted to pyruvate by the action of the enzyme glyoxal oxidase [85, 86]. The autoxidation of aminoacetone to MG, mediated by metal ions such as and , is considered a source of carbon-centered radicals and superoxide [87, 88]; similarly, the nonenzymatic reaction from acetoacetate to MG produces ROS, in the presence of myoglobin, hemoglobin, manganese, cytochrome c, or peroxidase [89, 90].
As reported in  and , ROS production related to MG has been identified in a very wide range of cellular systems, for example, vascular smooth muscle cells (VSMCs), endothelial cells, rat hepatocytes, platelet, neurons, and so forth. We have recently demonstrated that MG induces ROS production in primary culture of rat cardiomyocytes .
Moreover, MG is able to increase the activity of prooxidant enzymes [97–99] and to reduce antioxidants, in particular glutathione (GSH) and its enzymes [17, 100, 101]. Since the glyoxalase system that degrades MG uses reduced glutathione as a cofactor , decreased antioxidants in turn impair the detoxification of MG, leading to further oxidative damage.
It has been reported, furthermore, that MG can modify Cu,Zn superoxide dismutase (SOD) by covalent cross-linking, releasing copper ions from the enzyme and inactivating it . Other studies indicate that MG increases mitochondrial superoxide production [104, 105].
The correlation between ROS levels and MG concentration has been reported both in animals and cultured cells [43, 76, 77]. Commonly, in cell models, the administration of MG to the medium is followed by ROS level determination, that is often obtained by the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) assay or, seldom, by other tests such as lucigenin-linked chemiluminescence assay .
As previously reported, MG is the most reactive endogenous carbonyl able to generate AGEs. AGEs also induce oxidative stress through several mechanisms. AGEs stimulate production of cytokines and growth factors [62, 66, 107–111]. Moreover, AGEs bind to the AGE receptor (RAGE) and scavenger receptors to induce oxidative stress in various cells including VSMCs, endothelial cells, and mononuclear phagocytes . In endothelial cells, AGEs increase expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and increase activity of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) to increase oxidative stress [109, 113].
5. Methylglyoxal and Methylglyoxal-Derived AGE Deposits in AD
As both the extracellular A deposits and the intracellular NFTs have elevated stability and are long-lived proteins, they represent an ideal substrate for glycation . It has been suggested that the insolubility and protease resistance of -amyloid plaques are caused by extensive AGE-covalent protein cross-linking [4, 16]. In 1994, Vitek et al. observed, for the first time, that plaque fractions of AD brains contained about 3-fold more AGE adducts than preparations from healthy, age-matched controls. They showed that the in vivo half-life of -amyloid is prolonged in AD, resulting in greater accumulation of AGE modifications which in turn may act to promote accumulation of additional amyloid . An immunohistochemical study using a monoclonal antibody specific for AGE proteins showed extracellular AGE immunoreactivity in amyloid plaques in different cortical areas, in particular, primitive plaques, coronas of classic plaques and some glial cells in AD cortex were positive for AGEs . More recently, Fawver et al.  stained AD brain tissue for AGEs, and similar to the previous findings, AGEs were colocalized with amyloid plaques. In addition, Ko et al.  showed that APP was upregulated by AGEs in vitro and in vivo, and AGEs modulate APP expression through ROS. To explore whether glycated A is more toxic than authentic A, Li et al.  treated 8-DIV embryonic hippocampal neurons with A or A-AGE for 24 h. They found that A-AGE was more toxic than A in decreasing cell viability, increasing cell apoptosis, inducing tau hyperphosphorylation, and reducing synaptic proteins. It has also been observed that MG is not only capable of increasing the rate of production of -amyloid -sheets, oligomers and protofibrils but also of increasing the size of the aggregates .
The 4 allele of the apolipoprotein E (ApoE) is known as an important susceptibility gene for AD [118, 119]. It has been demonstrated that ApoE is codeposited in senile plaques in brains of patients with AD  and ApoE4 carriers present a higher A deposition in the form of senile plaques than noncarriers [121, 122]. Interestingly, AGEs colocalized to a very high degree with ApoE and ApoE4 exhibited a 3-fold greater AGE-binding activity than the ApoE3 isoform . The authors suggested that ApoE may participate in aggregate formation in the AD brain by binding to AGE-modified plaque components, which may explain why ApoE4 is associated with increased risk of AD.
As discussed above, AGEs can be localized intracellularly. Evidences have been provided that AGEs may accumulate in pyramidal neurons exhibiting a granular perikaryonal distribution in human brain whereas animals show a nuclear staining pattern . It has been shown that AGEs accumulate in endosomal and lysosomal vesicles of pyramidal neurons in the hippocampus, the dentate gyrus, cortical layers III, V, and VI, and in entorhinal cortical layers II, III, V, and VI . Interestingly, Wong et al.  observed colocalization of AGEs and inducible nitric oxide synthase (iNOS) in a few astrocytes in the upper neuronal layers in the early stage AD brains, while, in late AD brains, there was a much denser accumulation of astrocytes colocalized with AGEs and iNOS in the deeper and particularly upper neuronal layers. An immunohistochemical study showed that, in AD patients, the percentage of AGE-positive neurons (and astroglia) increases with the progression of the disease and those neurons which show diffuse cytosolic AGE immunoreactivity also contain hyperphosphorylated tau, suggesting a link between AGE accumulation and the formation of early neurofibrillary tangles . Using specific AGE antibodies directed against CML, pyrraline, and hexitol-lysine it has been demonstrated that AGEs are colocalized with NFTs [15, 127, 128].
In AD patients, AGEs accumulate also in the cerebrospinal fluid (CSF), which is in close contact with the brain. An increased accumulation of Amadori products in all major proteins of CSF of AD patients including albumin, apolipoprotein E, and transthyretin has been observed . Bär et al.  measured significantly elevated levels of CML in CSF of AD patients when compared to controls. In CSF protein, Ahmed et al.  observed an increased levels of CML residues in subjects with AD and in CSF ultrafiltrate; the concentrations of MG-derived hydroimidazolone free adducts were also increased.
6. Role of Methylglyoxal and Methylglyoxal-Derived AGEs in the Progression of AD
The process underlying AD is complex and involves many different features such as mitochondrial dysfunction, abnormal protein aggregation, inflammation, and excitotoxicity. Beeri et al.  conducted an interesting clinical study on 267 subjects, at least 75 years old, and cognitively intact at the beginning of the project. They demonstrated that the subjects with higher serum levels of MG had a faster rate of cognitive decline. Several potential mechanisms have been suggested to explain MG and MG-derived AGE neurotoxicity. Krautwald and Münch  suggested that AGEs contribute to the pathogenesis of AD in two different ways: cross-linking cytoskeletal proteins inducing neuronal dysfunction and death and accumulating on A deposits chronically activating micro- and astroglial cells, as widely underlined in the previous paragraph. Moreover, it has been observed that MG is a neurotoxic mediator of oxidative damage in the progression of AD and other neurodegenerative diseases . The brain is highly susceptible to oxidative stress due to its high energy demand, high oxygen consumption, large amounts of peroxidizable polyunsaturated fatty acids, and low levels of antioxidant enzymes . It is no wonder that ROS induced damage to biomolecules is widely reported in AD and increasing evidences suggest that oxidative stress plays a critical role in the disease . As the impairment of mitochondrial function is the main source of ROS generation and also a major target of oxidative damage, mitochondrial dysfunction has been implicated in AD [136, 137]. de Arriba et al.  demonstrated that MG may seriously affect mitochondrial respiration and the energetic status of cells. In particular, they observed that MG increases intracellular ROS and lactate production in SH-SY5Y neuroblastoma cells and decreases mitochondrial membrane potential and intracellular ATP levels. SH-SY5Y neuroblastoma cells have been extensively used to study the effect of MG as they show greater sensitivity to MG challenge, due to a defective antioxidant and detoxifying ability . Huang et al.  observed that MG induced Neuro-2A neuroblastoma cell line apoptosis via alternation of mitochondrial membrane potential and Bax/Bcl-2 ratio, activation of caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). Moreover, they investigated the mechanisms behind MG-induced neuronal cell apoptosis demonstrating that MG activates proapoptotic mitogen-activated protein kinase (MAPK) signaling pathways (JNK and p38). This data is in agreement with the results of Chen et al.  that, using primary cultures of rat hippocampal neurons, demonstrated that MG increases the expression level of cleaved caspase-3 and decreases Bcl-2/Bax ratio. As activated caspase-3 immunoreactivity is elevated in AD and exhibits a high degree of colocalization with NFTs and senile plaque in AD brain, it has been suggested that activated caspase-3 may be a factor in functional decline .
AGEs exert direct toxicity to cells through predominantly apoptotic mechanisms. Yin et al.  investigated the effects of AGEs in SH-SY5Y cells and rat cortical neurons. They observed that AGEs induce cell death increasing intracellular ROS through the increase of NADPH oxidase activity. Moreover, endoplasmic reticulum stress was triggered by AGE-induced oxidative stress, resulting in the activation of C/EBP homologous protein (CHOP) and caspase-12 that consequently initiates cell death. Tau phosphorylation is strictly controlled by the coordinated activities of tau phosphatase(s) and tau kinase(s), and the hyperphosphorylation of tau in the AD brain might be due to the overactive protein kinases and/or inactivation of protein phosphatases [142, 143]. Tau can be phosphorylated by different protein kinases such as the members of the MAPK family (JNK, p38 and Erk1/2), GSK-3, and cyclin-dependent kinase 5 (cdk5), while protein phosphatase (PP) 2A plays a major role in regulating dephosphorylating of the hyperphosphorylated tau isolated from the AD brains [143–147]. Using wild-type mouse N2a cells, Li et al.  observed that MG induces tau hyperphosphorylation and activates GSK-3 and p38, while the simultaneous inhibition of GSK-3 or p38 could attenuate MG-induced tau hyperphosphorylation, suggesting an important roles of GSK-3 and p38 in the MG-induced NTFs formation. On the other hand, an interesting proteomic study demonstrated a decreased level of PP2 in SH-SY5Y cells subjected to MG-induced oxidative stress. Thus, it could be speculated that MG has a double role in inducing tau hyperphosphorylation: enhancing kinase activities and reducing phosphatase level. Besides hyperphosphorylation, it has been suggested that carbonyl-derived posttranslational modifications of neurofilaments may account for the biochemical properties of NFTs, likely as a result of extensive cross-links [149, 150]. Kuhla et al. , in an in vitro experiment, incubated wild-type and seven pseudophosphorylated mutant tau proteins with MG and observed the formation of PHF-like structures. Interestingly, MG formed PHFs in a concentration-dependent manner and this process could be accelerated by hyperphosphorylation.
7. Redox Signaling Modulated by Methylglyoxal in AD
As previously highlighted, MG cytotoxicity to tissue or cells is mainly mediated through an increase of oxidative stress and an induction of apoptosis. Oxidative stress is thought to play a causative role in the development of AD [152, 153]. Such stress is a typical activator of two important MAPK pathways in AD: the JNK and the p38 signaling pathways . It has been suggested that the activation of the MAPK signaling pathways contributes to AD pathogenesis through different mechanisms including induction of apoptosis in neurons [155–158], activation of - and γ-secretases, [159, 160] and phosphorylation and stabilization of APP [161, 162]. Different studies have associated MG with MAPK pathways. In RAW 264.7 cells, MG stimulated the simultaneous activation of p44/42 and p38 MAPK and also stimulates the translocation to the cell membranes of another important protein kinase involved in cellular signaling: protein kinase C (PKC) . Moreover, Pal et al.  indicated that MG stimulates iNOS activation by p38 MAPK-NF--dependent pathway and ROS production by ERK and JNK activation in sarcoma-180 tumor bearing mice.
Regarding the implications of MAPK signaling pathway in oxidative damage leading to apoptosis, it has been observed that MG is able to induce apoptosis in PC12 cells through the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin/gamma-glutamylcysteine ligase catalytic subunit (PI3K/Akt/mTOR/GCLc)/redox signaling pathway. Huang et al.  indicated that MG-induced Neuro-2A cell apoptosis was mediated through activation of the MAPK signaling pathway mediated by p38 and JNK. Recently, Heimfarth et al.  demonstrated that the exposure of slices of cerebral cortex and hippocampus of new born rats to mM MG induced ROS production and cytotoxicity. In particular, they showed that the signaling pathway mediated by ERK is totally implicated in the ROS-mediated cytotoxic damage as the initial blockage of MEK/ERK signaling pathway might be useful for the protection of cells from the high ROS levels. Additionally, they observed that p38MAPK and JNK pathway activation is related with ROS-independent mechanisms leading to reduced cell viability and apoptotic cell death.
Moreover, as it has been underlined in the previous paragraph, the MG activation of GSK-3 and p38 MAPK induces AD tau hyperphosphorylation .
Many scientific evidences revealed different important actions of MG on signal transduction, redox balance, and cell energetic status as well as homeostatic control of cellular function. Elevated MG levels induce AGEs and ROS production playing a role in AD by several mechanisms (Figure 2). AGEs extensively cross-link proteins in A deposits and neurofilaments exacerbating AD pathological hallmarks. In particular, AGEs cross-link proteins in A deposits making them more insoluble, protease resistant, and more toxic. MG induces tau hyperphosphorylation by enhancing kinase activities and reducing phosphatase level. Moreover, MG is a neurotoxic mediators of oxidative stress in the progression of AD and is capable of activating many redox signaling pathways leading to apoptosis and cellular dysfunction. Accumulation of AGEs further magnifies ROS production by inducing the glycation of important antioxidant enzymes and by providing precursor of oxidative stress. In conclusion, it can be reasonably supposed that cognitive decline associated with AD might be strongly linked to an increase in MG levels due to an oxoaldehyde detoxification impairment or an altered endogenous oxoaldehyde production. From a clinical point of view, the reduction of risk factors for pathologies such as diabetes, characterized by MG accumulation due to hyperglycemic conditions and impaired glucose metabolism , and the enhancement of MG scavenging system may provide new therapeutic opportunities to reduce the pathophysiological modifications associated with carbonyl stress in AD.
|AGEs:||Advanced glycation end products|
|APP:||Amyloid- protein precursor|
|cdk5:||Cyclin-dependent kinase 5|
|CHOP:||C/EBP homologous protein|
|ICAM-1:||Intercellular adhesion molecule-1|
|iNOS:||Inducible nitric oxide synthase|
|MAP-tau:||Microtubule-associated tau protein|
|MAPK:||Mitogen activated protein kinase|
|MG-H:||Imidazolone adducts (methylglyoxal-derived hydroimidazolone)|
|MG-H2:||2-Amino-5-(2-amino-5-hydro-5-methyl-4-imidazolon-1-yl) pentanoic acid|
|MG-H3:||2-Amino-5-(2-amino-4-hydro-4-methyl-5-imidazolon-1-yl) pentanoic acid|
|MODIC:||2-Ammonio-6-(2-[(4-ammonio-5-oxido-5-oxopentyl) amino]-4-methyl-4, 5-dihydro-1H-imidazol-5-ylidene amino) hexanoate|
|NADPH:||Nicotinamide adenine dinucleotide phosphate|
|NF-B:||Nuclear factor kappa light chain enhancer of activated B cells|
|PARP:||Poly (ADP-ribose) polymerase|
|PHFs:||Paired helical filaments|
|PI3K/Akt/mTOR/GCLc:||Phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin/gamma-glutamylcysteine ligase catalytic subunit|
|PKC:||Protein kinase C|
|RAGE:||Receptor for AGEs|
|RNS:||Reactive nitrogen species|
|ROS:||Reactive oxygen species|
|SSAO:||Semicarbazide sensitive amine oxidase|
|VCAM-1:||Vascular cell adhesion molecule-1|
|VSMCs:||Vascular smooth muscle cells.|
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by MIUR-FIRB (Project RBAP11HSZS) and “Fondazione del Monte di Bologna e Ravenna” (Italy) (Cristina Angeloni and Silvana Hrelia).
- H. Zheng and E. H. Koo, “Biology and pathophysiology of the amyloid precursor protein,” Molecular Neurodegeneration, vol. 6, no. 1, article 27, 2011.
- D. M. Walsh, I. Klyubin, J. V. Fadeeva, M. J. Rowan, and D. J. Selkoe, “Amyloid-β oligomers: their production, toxicity and therapeutic inhibition,” Biochemical Society Transactions, vol. 30, no. 4, pp. 552–557, 2002.
- D. T. Loo, A. Copani, C. J. Pike, E. R. Whittemore, A. J. Walencewicz, and C. W. Cotman, “Apoptosis is induced by β-amyloid in cultured central nervous system neurons,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 17, pp. 7951–7955, 1993.
- A.-L. Bulteau, P. Verbeke, I. Petropoulos, A.-F. Chaffotte, and B. Friguet, “Proteasome inhibition in glyoxal-treated fibroblasts and resistance of glycated glucose-6-phosphate dehydrogenase to 20 S proteasome degradation in vitro,” The Journal of Biological Chemistry, vol. 276, no. 49, pp. 45662–45668, 2001.
- P. S. Sachdev, L. Zhuang, N. Braidy, and W. Wen, “Is Alzheimer's a disease of the white matter?” Current Opinion in Psychiatry, vol. 26, no. 3, pp. 244–251, 2013.
- D. W. Cleveland, S. Y. Hwo, and M. W. Kirschner, “Purification of tau, a microtubule associated protein that induces assembly of microtubules from purified tubulin,” Journal of Molecular Biology, vol. 116, no. 2, pp. 207–225, 1977.
- R. Brandt and G. Lee, “Functional organization of microtubule-associated protein tau. Identification of regions which affect microtubule growth, nucleation, and bundle formation in vitro,” The Journal of Biological Chemistry, vol. 268, no. 5, pp. 3414–3419, 1993.
- G. Münch, J. Thome, P. Foley, R. Schinzel, and P. Riederer, “Advanced glycation endproducts in ageing and Alzheimer's disease,” Brain Research Reviews, vol. 23, no. 1-2, pp. 134–143, 1997.
- P. Ulrich and A. Cerami, “Protein glycation, diabetes, and aging,” Recent Progress in Hormone Research, vol. 56, pp. 1–21, 2001.
- P. J. Thornalley, “Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification—a role in pathogenesis and antiproliferative chemotherapy,” General Pharmacology, vol. 27, no. 4, pp. 565–573, 1996.
- P. J. Thornalley, “Dicarbonyl intermediates in the Maillard reaction,” Annals of the New York Academy of Sciences, vol. 1043, pp. 111–117, 2005.
- R. Ramasamy, S. J. Vannucci, S. S. D. Yan, K. Herold, S. F. Yan, and A. M. Schmidt, “Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation,” Glycobiology, vol. 15, no. 7, pp. 16R–28R, 2005.
- K. Chen, J. Maley, and P. H. Yu, “Potential implications of endogenous aldehydes in β-amyloid misfolding, oligomerization and fibrillogenesis,” Journal of Neurochemistry, vol. 99, no. 5, pp. 1413–1424, 2006.
- J. N. Fawver, H. E. Schall, R. D. P. Chapa, X. Zhu, and I. V. Murray, “Amyloid-beta metabolite sensing: biochemical linking of glycation modification and misfolding,” Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 63–73, 2012.
- R. J. Castellani, P. L. R. Harris, L. M. Sayre et al., “Active glycation in neurofibrillary pathology of Alzheimer disease: Nε-(Carboxymethyl) lysine and hexitol-lysine,” Free Radical Biology and Medicine, vol. 31, no. 2, pp. 175–180, 2001.
- H.-J. Lüth, V. Ogunlade, B. Kuhla et al., “Age- and stage-dependent accumulation of advanced glycation end products in intracellular deposits in normal and Alzheimer's disease brains,” Cerebral Cortex, vol. 15, no. 2, pp. 211–220, 2005.
- F. Amicarelli, S. Colafarina, F. Cattani et al., “Scavenging system efficiency is crucial for cell resistance to ROS-mediated methylglyoxal injury,” Free Radical Biology and Medicine, vol. 35, no. 8, pp. 856–871, 2003.
- S. Kikuchi, K. Shinpo, F. Moriwaka, Z. Makita, T. Miyata, and K. Tashiro, “Neurotoxicity of methylglyoxal and 3-deoxyglucosone on cultured cortical neurons: synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases,” Journal of Neuroscience Research, vol. 57, no. 2, pp. 280–289, 1999.
- K. Shinpo, S. Kikuchi, H. Sasaki, A. Ogata, F. Moriwaka, and K. Tashiro, “Selective vulnerability of spinal motor neurons to reactive dicarbonyl compounds, intermediate products of glycation, in vitro: implication of inefficient glutathione system in spinal motor neurons,” Brain Research, vol. 861, no. 1, pp. 151–159, 2000.
- D. A. Butterfield and C. M. Lauderback, “Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid β-peptide-associated free radical oxidative stress,” Free Radical Biology and Medicine, vol. 32, no. 11, pp. 1050–1060, 2002.
- C. E. Cross, B. Halliwell, E. T. Borish et al., “Oxygen radicals and human disease. Davis conference,” Annals of Internal Medicine, vol. 107, no. 4, pp. 526–545, 1987.
- W. R. Markesbery, “Oxidative stress hypothesis in Alzheimer's disease,” Free Radical Biology and Medicine, vol. 23, no. 1, pp. 134–147, 1997.
- A. Tarozzi, C. Angeloni, M. Malaguti, F. Morroni, S. Hrelia, and P. Hrelia, “Sulforaphane as a potential protective phytochemical against neurodegenerative diseases,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 415078, 10 pages, 2013.
- A. Y. Abramov, L. Canevari, and M. R. Duchen, “β-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase,” Journal of Neuroscience, vol. 24, no. 2, pp. 565–575, 2004.
- E. Motori, J. Puyal, N. Toni et al., “Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance,” Cell Metabolism, vol. 18, no. 6, pp. 844–859, 2013.
- M. S. Silva, R. A. Gomes, A. E. Ferreira, A. P. Freire, and C. Cordeiro, “The glyoxalase pathway: the first hundred years... and beyond,” The Biochemical Journal, vol. 453, no. 1, pp. 1–15, 2013.
- I. Nemet, L. Varga-Defterdarović, and Z. Turk, “Methylglyoxal in food and living organisms,” Molecular Nutrition and Food Research, vol. 50, no. 12, pp. 1105–1117, 2006.
- J. Wang and T. Chang, “Methylglyoxal content in drinking coffee as a cytotoxic factor,” Journal of Food Science, vol. 75, no. 6, pp. H167–H171, 2010.
- M. P. Kalapos, “Where does plasma methylglyoxal originate from?” Diabetes Research and Clinical Practice, vol. 99, no. 3, pp. 260–271, 2013.
- G. Vistoli, D. De Maddis, A. Cipak, N. Zarkovic, M. Carini, and G. Aldini, “Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation,” Free Radical Research, vol. 47, no. S1, pp. 3–27, 2013.
- J. Degen, M. Hellwig, and T. Henle, “1,2-dicarbonyl compounds in commonly consumed foods,” Journal of Agricultural and Food Chemistry, vol. 60, no. 28, pp. 7071–7079, 2012.
- Y. V. Pfeifer, P. T. Haase, and L. W. Kroh, “Reactivity of thermally treated alpha-dicarbonyl compounds,” Journal of Agricultural and Food Chemistry, vol. 61, no. 12, pp. 3090–3096, 2013.
- I. Nemet and L. Varga-Defterdarović, “Methylglyoxal-derived β-carbolines formed from tryptophan and its derivates in the Maillard reaction,” Amino Acids, vol. 32, no. 2, pp. 291–293, 2007.
- S. Kuntz, S. Rudloff, J. Ehl, R. G. Bretzel, and C. Kunz, “Food derived carbonyl compounds affect basal and stimulated secretion of interleukin-6 and -8 in Caco-2 cells,” European Journal of Nutrition, vol. 48, no. 8, pp. 499–503, 2009.
- J. P. Casazza, M. E. Felver, and R. L. Veech, “The metabolism of acetone in rat,” The Journal of Biological Chemistry, vol. 259, no. 1, pp. 231–236, 1984.
- R. A. Cooper, “Metabolism of methylglyoxal in microorganisms,” Annual Review of Microbiology, vol. 38, pp. 49–68, 1984.
- K. Fujioka and T. Shibamoto, “Determination of toxic carbonyl compounds in cigarette smoke,” Environmental Toxicology, vol. 21, no. 1, pp. 47–54, 2006.
- V. Camel and A. Bermond, “The use of ozone and associated oxidation processes in drinking water treatment,” Water Research, vol. 32, no. 11, pp. 3208–3222, 1998.
- T.-M. Fu, D. J. Jacob, F. Wittrock, J. P. Burrows, M. Vrekoussis, and D. K. Henze, “Global budgets of atmospheric glyoxal and methylglyoxal, and implications for formation of secondary organic aerosols,” Journal of Geophysical Research D, vol. 113, no. 15, Article ID D15303, 2008.
- M. P. Kalapos, “Methylglyoxal in living organisms—chemistry, biochemistry, toxicology and biological implications,” Toxicology Letters, vol. 110, no. 3, pp. 145–175, 1999.
- P. J. Beisswenger, S. K. Howell, R. G. Nelson, M. Mauer, and B. S. Szwergold, “α-oxoaldehyde metabolism and diabetic complications,” Biochemical Society Transactions, vol. 31, part 6, pp. 1358–1363, 2003.
- M. P. Kalapos, “Methylglyoxal and glucose metabolism: a historical perspective and future avenues for research,” Drug Metabolism and Drug Interactions, vol. 23, no. 1-2, pp. 69–91, 2008.
- M. P. Kalapos, “The tandem of free radicals and methylglyoxal,” Chemico-Biological Interactions, vol. 171, no. 3, pp. 251–271, 2008.
- Q. Cui and M. Karplus, “Catalysis and specificity in enzymes: a study of triosephosphate isomerase and comparison with methyl glyoxal synthase,” Advances in Protein Chemistry, vol. 66, pp. 315–372, 2003.
- J. P. Richard, “Mechanism for the formation of methylglyoxal from triosephosphates,” Biochemical Society Transactions, vol. 21, no. 2, pp. 549–553, 1993.
- R. A. Cooper, “ Methylglyoxal synthase,” Methods in Enzymology, vol. 41, pp. 502–508, 1975.
- A. Dhar, K. Desai, M. Kazachmov, P. Yu, and L. Wu, “Methylglyoxal production in vascular smooth muscle cells from different metabolic precursors,” Metabolism: Clinical and Experimental, vol. 57, no. 9, pp. 1211–1220, 2008.
- F. Y. Bondoc, Z. Bao, W.-Y. Hu et al., “Acetone catabolism by cytochrome P450 2E1: studies with CYP2E1-null mice,” Biochemical Pharmacology, vol. 58, no. 3, pp. 461–463, 1999.
- Z. Turk, I. Nemet, L. Varga-Defteardarovic, and N. Car, “Elevated level of methylglyoxal during diabetic ketoacidosis and its recovery phase,” Diabetes and Metabolism, vol. 32, no. 2, pp. 176–180, 2006.
- J.-Y. Jung, H. S. Yun, J. Lee, and M.-K. Oh, “Production of 1,2-propanediol from glycerol in saccharomyces cerevisiae,” Journal of Microbiology and Biotechnology, vol. 21, no. 8, pp. 846–853, 2011.
- T. Shibamoto, “Analytical methods for trace levels of reactive carbonyl compounds formed in lipid peroxidation systems,” Journal of Pharmaceutical and Biomedical Analysis, vol. 41, no. 1, pp. 12–25, 2006.
- H. Esterbauer, K. H. Cheeseman, and M. U. Dianzani, “Separation and characterization of the aldehydic products of lipid peroxidation stimulated by ADP-Fe2+ in rat liver microsomes,” The Biochemical Journal, vol. 208, no. 1, pp. 129–140, 1982.
- P. J. Thornalley, “The glyoxalase system in health and disease,” Molecular Aspects of Medicine, vol. 14, no. 4, pp. 287–371, 1993.
- G. A. Lyles and J. Chalmers, “The metabolism of aminoacetone to methylglyoxal by semicarbazide-sensitive amine oxidase in human umbilical artery,” Biochemical Pharmacology, vol. 43, no. 7, pp. 1409–1414, 1992.
- E. J. H. Bechara, F. Dutra, V. E. S. Cardoso et al., “The dual face of endogenous α-aminoketones: pro-oxidizing metabolic weapons,” Comparative Biochemistry and Physiology C, vol. 146, no. 1-2, pp. 88–110, 2007.
- B. A. Callingham, A. E. Crosbie, and B. A. Rous, “Some aspects of the pathophysiology of semicarbazide-sensitive amine oxidase enzymes,” Progress in Brain Research, vol. 106, pp. 305–321, 1995.
- G. A. Lyles, “Mammalian plasma and tissue-bound semicarbazide-sensitive amine oxidases: biochemical, pharmacological and toxicological aspects,” International Journal of Biochemistry and Cell Biology, vol. 28, no. 3, pp. 259–274, 1996.
- P. J. Thornalley, “Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems—role in ageing and disease,” Drug Metabolism and Drug Interactions, vol. 23, no. 1-2, pp. 125–150, 2008.
- P. J. Thornalley, A. Langborg, and H. S. Minhas, “Formation of glyoxal, methylglyoxal and 8-deoxyglucosone in the glycation of proteins by glucose,” The Biochemical Journal, vol. 344, part 1, pp. 109–116, 1999.
- P. J. Thornalley, S. Battah, N. Ahmed et al., “Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry,” The Biochemical Journal, vol. 375, part 3, pp. 581–592, 2003.
- N. Ahmed, P. J. Thornalley, J. Dawczynski et al., “Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins,” Investigative Ophthalmology and Visual Science, vol. 44, no. 12, pp. 5287–5292, 2003.
- T. Oya, N. Hattori, Y. Mizuno et al., “Methylglyoxal modification of protein. Chemical and immunochemical characterization of methylglyoxal-arginine adducts,” The Journal of Biological Chemistry, vol. 274, no. 26, pp. 18492–18502, 1999.
- I. N. Shipanova, M. A. Glomb, and R. H. Nagaraj, “Protein modification by methylglyoxal: chemical nature and synthetic mechanism of a major fluorescent adduct,” Archives of Biochemistry and Biophysics, vol. 344, no. 1, pp. 29–36, 1997.
- E. B. Frye, T. P. Degenhardt, S. R. Thorpe, and J. W. Baynes, “Role of the Maillard reaction in aging of tissue proteins: advanced glycation end product-dependent increase in imidazolium cross-links in human lens proteins,” The Journal of Biological Chemistry, vol. 273, no. 30, pp. 18714–18719, 1998.
- K. M. Bieme, D. Alexander Fried, and M. O. Lederer, “Identification and quantification of major maillard cross-links in human serum albumin and lens protein: evidence for glucosepane as the dominant compound,” The Journal of Biological Chemistry, vol. 277, no. 28, pp. 24907–24915, 2002.
- T. W. C. Lo, M. E. Westwood, A. C. McLellan, T. Selwood, and P. J. Thornalley, “Binding and modification of proteins by methylglyoxal under physiological conditions: a kinetic and mechanistic study with Nα-acetylarginine, Nα- acetylcysteine, and Nα-acetyllysine, and bovine serum albumin,” The Journal of Biological Chemistry, vol. 269, no. 51, pp. 32299–32305, 1994.
- N. Ahmed, D. Dobler, M. Dean, and P. J. Thornalley, “Peptide mapping identifies hotspot site of modification in human serum albumin by methylglyoxal involved in ligand binding and esterase activity,” The Journal of Biological Chemistry, vol. 280, no. 7, pp. 5724–5732, 2005.
- E. Kaufmann, B. O. Boehm, S. D. Süssmuth et al., “The advanced glycation end-product Nε-(carboxymethyl)lysine level is elevated in cerebrospinal fluid of patients with amyotrophic lateral sclerosis,” Neuroscience Letters, vol. 371, no. 2-3, pp. 226–229, 2004.
- L. Southern, J. Williams, and M. M. Esiri, “Immunohistochemical study of N-epsilon-carboxymethyl lysine (CML) in human brain: relation to vascular dementia,” BMC Neurology, vol. 7, article 35, 2007.
- M. Krautwald and G. Münch, “Advanced glycation end products as biomarkers and gerontotoxins—a basis to explore methylglyoxal-lowering agents for Alzheimer's disease?” Experimental Gerontology, vol. 45, no. 10, pp. 744–751, 2010.
- T. Jono, T. Kimura, J. Takamatsu et al., “Accumulation of imidazolone, pentosidine and Nε-(carboxymethyl)lysine in hippocampal CA4 pyramidal neurons of aged human brain,” Pathology International, vol. 52, no. 9, pp. 563–571, 2002.
- N. Ahmed, U. Ahmed, P. J. Thornalley, K. Hager, G. Fleischer, and G. Münch, “Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer's disease and link to cognitive impairment,” Journal of Neurochemistry, vol. 92, no. 2, pp. 255–263, 2005.
- N. Taniguchi, M. Takahashi, H. Sakiyama et al., “A common pathway for intracellular reactive oxygen species production by glycoxidative and nitroxidative stress in vascular endothelial cells and smooth muscle cells,” Annals of the New York Academy of Sciences, vol. 1043, pp. 521–528, 2005.
- K. M. Desai and L. Wu, “Free radical generation by methylglyoxal in tissues,” Drug Metabolism and Drug Interactions, vol. 23, no. 1-2, pp. 151–173, 2008.
- L. F. Dmitriev and V. N. Titov, “Lipid peroxidation in relation to ageing and the role of endogenous aldehydes in diabetes and other age-related diseases,” Ageing Research Reviews, vol. 9, no. 2, pp. 200–210, 2010.
- T. Chang and L. Wu, “Methylglyoxal, oxidative stress, and hypertension,” Canadian Journal of Physiology and Pharmacology, vol. 84, no. 12, pp. 1229–1238, 2006.
- I. Dhar and K. Desai, “Chapter 30. Aging: drugs to eliminate methylglyoxal, a reactive glucose metabolite, and advanced glycation endproducts,” in Pharmacology, L. Gallelli, Ed., 2012.
- M. P. Kalapos, K. M. Desai, and L. Wu, “Methylglyoxal, oxidative stress, and aging,” in Aging and Age-Related Disorders, Oxidative Stress in Applied Basic Research and Clinical Practice, pp. 149–167, Humana Press, 2010.
- X. Huang, F. Wang, W. Chen, Y. Chen, N. Wang, and K. von Maltzan, “Possible link between the cognitive dysfunction associated with diabetes mellitus and the neurotoxicity of methylglyoxal,” Brain Research, vol. 1469, pp. 82–91, 2012.
- A. Szent-Gyorgyi, Bioelectronics: A Study in cellular regulations, Defense, and cancer, Academic Press, New York, NY, USA, 1968.
- H. Kon and A. Szent Gyorgyi, “Charge transfer between amine and carbonyl,” Proceedings of the National Academy of Sciences of the United States of America, vol. 70, no. 11, pp. 3139–3140, 1973.
- M. P. Kalapos, A. Littauer, and H. De Groot, “Has reactive oxygen a role in methylglyoxal toxicity? A study on cultured rat hepatocytes,” Archives of Toxicology, vol. 67, no. 5, pp. 369–372, 1993.
- P. H. Yu, S. Wright, E. H. Fan, Z.-R. Lun, and D. Gubisne-Harberle, “Physiological and pathological implications of semicarbazide-sensitive amine oxidase,” Biochimica et Biophysica Acta, vol. 1647, no. 1-2, pp. 193–199, 2003.
- J. M. Johnson, H. B. Halsall, and W. R. Heineman, “Redox activation of galactose oxidase: thin-layer electrochemical study,” Biochemistry, vol. 24, no. 7, pp. 1579–1585, 1985.
- P. J. Kersten and T. K. Kirk, “Involvement of a new enzyme, glyoxal oxidase, in extracellular H2O2 production by phanerochaete chrysosporium,” Journal of Bacteriology, vol. 169, no. 5, pp. 2195–2201, 1987.
- B. Leuthner, C. Aichinger, E. Oehmen et al., “A H2O2-producing glyoxal oxidase is required for filamentous growth and pathogenicity in Ustilago maydis,” Molecular Genetics and Genomics, vol. 272, no. 6, pp. 639–650, 2005.
- Y. Hiraku, J. Sugimoto, T. Yamaguchi, and S. Kawanishi, “Oxidative DNA damage induced by aminoacetone, an amino acid metabolite,” Archives of Biochemistry and Biophysics, vol. 365, no. 1, pp. 62–70, 1999.
- F. Dutra, F. S. Knudsen, D. Curi, and E. J. H. Bechara, “Aerobic oxidation of aminoacetone, a threonine catabolite: iron catalysis and coupled iron release from ferritin,” Chemical Research in Toxicology, vol. 14, no. 9, pp. 1323–1329, 2001.
- C. C. C. Vidigal and G. Cilento, “Evidence for the generation of excited methylglyoxal in the myoglobin catalyzed oxidation of acetoacetate,” Biochemical and Biophysical Research Communications, vol. 62, no. 2, pp. 184–190, 1975.
- K. Takayama, M. Nakano, and K. Zinner, “Generation of electronic energy in the myoglobin catalyzed oxidation of acetoacetate to methylglyoxal,” Archives of Biochemistry and Biophysics, vol. 176, no. 2, pp. 663–670, 1976.
- T. Yamaguchi and K. Nakagawa, “Mutagenicity of and formation of oxygen radicals by trioses and glyoxal derivatives,” Agricultural and Biological Chemistry, vol. 47, no. 11, pp. 2461–2465, 1983.
- P. Thornalley, S. Wolff, J. Crabbe, and A. Stern, “The autoxidation of glyceraldehyde and other simple monosaccharides under physiological conditions catalysed by buffer ions,” Biochimica et Biophysica Acta, vol. 797, no. 2, pp. 276–287, 1984.
- P. J. Thornalley, S. P. Wolff, M. J. Crabbe, and A. Stern, “The oxidation of oxyhaemoglobin by glyceraldehyde and other simple monosaccharides,” The Biochemical Journal, vol. 217, no. 3, pp. 615–622, 1984.
- R. Atkinson, W. P. L. Carter, K. R. Darnall, M. Winer, and J. N. Pitts, “A smog chamber and modeling study of the gas phase NOx—air photooxidation of toluene and the cresols,” International Journal of Chemical Kinetics, vol. 12, no. 11, pp. 779–836, 1980.
- H. Nukaya, Y. Inaoka, H. Ishida et al., “Modification of the amino group of guanosine by methylglyoxal and other α-ketoaldehydes in the presence of hydrogen peroxide,” Chemical and Pharmaceutical Bulletin, vol. 41, no. 4, pp. 649–653, 1993.
- C. Angeloni, S. Turroni, L. Bianchi et al., “Novel targets of sulforaphane in primary cardiomyocytes identified by proteomic analysis,” PLoS ONE, vol. 8, no. 12, Article ID e83283, 2013.
- T. Chang, R. Wang, and L. Wu, “Methylglyoxal-induced nitric oxide and peroxynitrite production in vascular smooth muscle cells,” Free Radical Biology and Medicine, vol. 38, no. 2, pp. 286–293, 2005.
- C. Ho, P.-H. Lee, W.-J. Huang, Y.-C. Hsu, C.-L. Lin, and J.-Y. Wang, “Methylglyoxal-induced fibronectin gene expression through ras-mediated NADPH oxidase activation in renal mesangial cells,” Nephrology, vol. 12, no. 4, pp. 348–356, 2007.
- R. A. Ward and K. R. McLeish, “Methylglyoxal: a stimulus to neutrophil oxygen radical production in chronic renal failure?” Nephrology Dialysis Transplantation, vol. 19, no. 7, pp. 1702–1707, 2004.
- J. Nicolay, J. Schneider, O. Niemoeller et al., “Stimulation of suicidal erythrocyte death by methylglyoxal,” Cellular Physiology and Biochemistry, vol. 18, no. 4-5, pp. 223–232, 2006.
- Y. S. Park, Y. H. Koh, M. Takahashi et al., “Identification of the binding site of methylglyoxal on gluthathione peroxidase: methylglyoxal inhibits glutathione peroxidase activity via binding to glutathione binding sites Arg 184 and 185,” Free Radical Research, vol. 37, no. 2, pp. 205–211, 2003.
- P. J. Thornalley, “Glutathione-dependent detoxification of α-oxoaldehydes by the glyoxalase system: Involvement in disease mechanisms and antiproliferative activity of glyoxalase I inhibitors,” Chemico-Biological Interactions, vol. 111-112, pp. 137–151, 1998.
- J. H. Kang, “Modification and inactivation of human Cu,Zn-superoxide dismutase by methylglyoxal,” Molecules and Cells, vol. 15, no. 2, pp. 194–199, 2003.
- N. Rabbani and P. J. Thornalley, “Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress,” Biochemical Society Transactions, vol. 36, part5, pp. 1045–1050, 2008.
- M. G. Rosca, T. G. Mustata, M. T. Kinter et al., “Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation,” The American Journal of Physiology: Renal Physiology, vol. 289, no. 2, pp. F420–F430, 2005.
- J. Du, H. Suzuki, F. Nagase et al., “Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process,” Free Radical Biology and Medicine, vol. 31, no. 4, pp. 469–478, 2001.
- G. Basta, G. Lazzerini, M. Massaro et al., “Advanced glycation end products activate endothelium through signal-transduction receptor RAGE a mechanism for amplification of inflammatory responses,” Circulation, vol. 105, no. 7, pp. 816–822, 2002.
- J. Chen, S. V. Brodsky, D. M. Goligorsky et al., “Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells,” Circulation Research, vol. 90, no. 12, pp. 1290–1298, 2002.
- S. Kikuchi, K. Shinpo, M. Takeuchi et al., “Glycation—a sweet tempter for neuronal death,” Brain Research Reviews, vol. 41, no. 2-3, pp. 306–323, 2003.
- M.-P. Wautier, O. Chappey, S. Corda, D. M. Stern, A. M. Schmidt, and J.-L. Wautier, “Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE,” The American Journal of Physiology: Endocrinology and Metabolism, vol. 280, no. 5, pp. E685–E694, 2001.
- M. E. Westwood and P. J. Thornalley, “Induction of synthesis and secretion of interleukin 1β in the human monocytic THP-1 cells by human serum albumins modified with methylglyoxal and advanced glycation endproducts,” Immunology Letters, vol. 50, no. 1-2, pp. 17–21, 1996.
- P. J. Thornalley, “Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs,” Cellular and Molecular Biology, vol. 44, no. 7, pp. 1013–1023, 1998.
- A. Bierhaus, S. Chevion, M. Chevion et al., “Advanced glycation end product-induced activation of NF-κB is suppressed by α-lipoic acid in cultured endothelial cells,” Diabetes, vol. 46, no. 9, pp. 1481–1490, 1997.
- M. P. Vitek, K. Bhattacharya, J. M. Glendening et al., “Advanced glycation end products contribute to amyloidosis in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 11, pp. 4766–4770, 1994.
- T. Kimura, J. Takamatsu, N. Araki et al., “Are advanced glycation end-products associated with amyloidosis in Alzheimer's disease?” NeuroReport, vol. 6, no. 6, pp. 866–868, 1995.
- S.-Y. Ko, Y.-P. Lin, Y.-S. Lin, and S.-S. Chang, “Advanced glycation end products enhance amyloid precursor protein expression by inducing reactive oxygen species,” Free Radical Biology and Medicine, vol. 49, no. 3, pp. 474–480, 2010.
- X. H. Li, L. L. Du, X. S. Cheng et al., “Glycation exacerbates the neuronal toxicity of beta-amyloid,” Cell Death and Disease, vol. 4, article e673, 2013.
- H. M. Schipper, “Apolipoprotein E: implications for AD neurobiology, epidemiology and risk assessment,” Neurobiology of Aging, vol. 32, no. 5, pp. 778–790, 2011.
- G. Bu, “Apolipoprotein e and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy,” Nature Reviews Neuroscience, vol. 10, no. 5, pp. 333–344, 2009.
- Y. Namba, M. Tomonaga, H. Kawasaki, E. Otomo, and K. Ikeda, “Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease,” Brain Research, vol. 541, no. 1, pp. 163–166, 1991.
- E. Kok, S. Haikonen, T. Luoto et al., “Apolipoprotein E-dependent accumulation of alzheimer disease-related lesions begins in middle age,” Annals of Neurology, vol. 65, no. 6, pp. 650–657, 2009.
- T. Polvikoski, R. Sulkava, M. Haltia et al., “Apolipoprotein E, dementia, and cortical deposition of β-amyloid protein,” The New England Journal of Medicine, vol. 333, no. 19, pp. 1242–1247, 1995.
- Y. M. Li and D. W. Dickson, “Enhanced binding of advanced glycation endproducts (AGE) by the ApoE4 isoform links the mechanism of plaque deposition in Alzheimer's disease,” Neuroscience Letters, vol. 226, no. 3, pp. 155–158, 1997.
- G. Münch, B. Westcott, T. Menini, and A. Gugliucci, “Advanced glycation endproducts and their pathogenic roles in neurological disorders,” Amino Acids, vol. 42, no. 4, pp. 1221–1236, 2012.
- J. J. Li, M. Surini, S. Catsicas, E. Kawashima, and C. Bouras, “Age-dependent accumulation of advanced glycosylation end products in human neurons,” Neurobiology of Aging, vol. 16, no. 1, pp. 69–76, 1995.
- A. Wong, H.-J. Lüth, W. Deuther-Conrad et al., “Advanced glycation endproducts co-localize with inducible nitric oxide synthase in Alzheimer's disease,” Brain Research, vol. 920, no. 1-2, pp. 32–40, 2001.
- V. Prakash Reddy, M. E. Obrenovich, C. S. Atwood, G. Perry, and M. A. Smith, “Involvement of Maillard reactions in Alzheimer disease,” Neurotoxicity Research, vol. 4, no. 3, pp. 191–209, 2002.
- M. A. Smith, S. Taneda, P. L. Richey et al., “Advanced Maillard reaction end products are associated with Alzheimer disease pathology,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 12, pp. 5710–5714, 1994.
- V. V. Shuvaev, I. Laffont, J.-M. Serot, J. Fujii, N. Taniguchi, and G. Siest, “Increased protein glycation in cerebrospinal fluid of Alzheimer's disease,” Neurobiology of Aging, vol. 22, no. 3, pp. 397–402, 2001.
- K. J. Bär, S. Franke, B. Wenda et al., “Pentosidine and Nε-(carboxymethyl)-lysine in Alzheimer's disease and vascular dementia,” Neurobiology of Aging, vol. 24, no. 2, pp. 333–338, 2003.
- L. Mucke, “Neuroscience: Alzheimer's disease,” Nature, vol. 461, no. 7266, pp. 895–897, 2009.
- M. S. Beeri, E. Moshier, J. Schmeidler et al., “Serum concentration of an inflammatory glycotoxin, methylglyoxal, is associated with increased cognitive decline in elderly individuals,” Mechanisms of Ageing and Development, vol. 132, no. 11-12, pp. 583–587, 2011.
- M. A. Lovell, C. Xie, and W. R. Markesbery, “Acrolein is increased in Alzheimer's disease brain and is toxic to primary hippocampal cultures,” Neurobiology of Aging, vol. 22, no. 2, pp. 187–194, 2001.
- J. K. Andersen, “Oxidative stress in neurodegeneration: cause or consequence?” Nature Medicine, vol. 5, pp. S18–S25, 2004.
- A. Nunomura, G. Perry, G. Aliev et al., “Oxidative damage is the earliest event in Alzheimer disease,” Journal of Neuropathology and Experimental Neurology, vol. 60, no. 8, pp. 759–767, 2001.
- R. H. Swerdlow, “Brain aging, Alzheimer's disease, and mitochondria,” Biochimica et Biophysica Acta, vol. 1812, no. 12, pp. 1630–1639, 2011.
- P. F. Good, P. Werner, A. Hsu, C. W. Olanow, and D. P. Perl, “Evidence for neuronal oxidative damage in Alzheimer's disease,” The American Journal of Pathology, vol. 149, no. 1, pp. 21–28, 1996.
- S. G. de Arriba, G. Stuchbury, J. Yarin, J. Burnell, C. Loske, and G. Münch, “Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal cells-protection by carbonyl scavengers,” Neurobiology of Aging, vol. 28, no. 7, pp. 1044–1050, 2007.
- S.-M. Huang, H.-C. Chuang, C.-H. Wu, and G.-C. Yen, “Cytoprotective effects of phenolic acids on methylglyoxal-induced apoptosis in Neuro-2A cells,” Molecular Nutrition and Food Research, vol. 52, no. 8, pp. 940–949, 2008.
- Y.-J. Chen, X.-B. Huang, Z.-X. Li, L.-L. Yin, W.-Q. Chen, and L. Li, “Tenuigenin protects cultured hippocampal neurons against methylglyoxal-induced neurotoxicity,” European Journal of Pharmacology, vol. 645, no. 1–3, pp. 1–8, 2010.
- Q. Q. Yin, C. F. Dong, S. Q. Dong et al., “AGEs induce cell death via oxidative and endoplasmic reticulum stresses in both human SH-SY5Y neuroblastoma cells and rat cortical neurons,” Cellular and Molecular Neurobiology, vol. 32, no. 8, pp. 1299–1309, 2012.
- F. Liu, Z. Liang, and C. X. Gong, “Hyperphosphorylation of tau and protein phosphatases in Alzheimer disease,” Panminerva Medica, vol. 48, no. 2, pp. 97–108, 2006.
- K. Iqbal, F. Liu, C.-X. Gong, A. C. del Alonso, and I. Grundke-Iqbal, “Mechanisms of tau-induced neurodegeneration,” Acta Neuropathologica, vol. 118, no. 1, pp. 53–69, 2009.
- E. Planel, T. Miyasaka, T. Launey et al., “Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer's disease,” Journal of Neuroscience, vol. 24, no. 10, pp. 2401–2411, 2004.
- M. Hu, J. F. Waring, M. Gopalakrishnan, and J. Li, “Role of GSK-3β activation and α7 nAChRs in Aβ 1-42-induced tau phosphorylation in PC12 cells,” Journal of Neurochemistry, vol. 106, no. 3, pp. 1371–1377, 2008.
- C. X. Gong, “Dephosphorylation of Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A,” Neuroscience, vol. 61, no. 4, pp. 765–772, 1994.
- J.-Z. Wang, C.-X. Gong, T. Zaidi, I. Grundke-Iqbal, and K. Iqbal, “Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B,” The Journal of Biological Chemistry, vol. 270, no. 9, pp. 4854–4860, 1995.
- X. H. Li, J. Z. Xie, X. Jiang et al., “Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation,” NeuroMolecular Medicine, vol. 14, no. 4, pp. 338–348, 2012.
- M. A. Smith, M. Rudnicka-Nawrot, P. L. Richey et al., “Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer's disease,” Journal of Neurochemistry, vol. 64, no. 6, pp. 2660–2666, 1995.
- P. Cras, M. A. Smith, P. L. Richey, S. L. Siedlak, P. Mulvihill, and G. Perry, “Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross linking in Alzheimer disease,” Acta Neuropathologica, vol. 89, no. 4, pp. 291–295, 1995.
- B. Kuhla, C. Haase, K. Flach, H. J. Luth, T. Arendt, and G. Munch, “Effect of pseudophosphorylation and cross-linking by lipid peroxidation and advanced glycation end product precursors on tau aggregation and filament formation,” J Biol Chem, vol. 282, no. 10, pp. 6984–6991, 2007.
- M. T. Lin and M. F. Beal, “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases,” Nature, vol. 443, no. 7113, pp. 787–795, 2006.
- D. Praticò, “Oxidative stress hypothesis in Alzheimer's disease: a reappraisal,” Trends in Pharmacological Sciences, vol. 29, no. 12, pp. 609–615, 2008.
- X. Zhu, H.-G. Lee, A. K. Raina, G. Perry, and M. A. Smith, “The role of mitogen-activated protein kinase pathways in Alzheimer's disease,” NeuroSignals, vol. 11, no. 5, pp. 270–281, 2002.
- A. Chiarini, I. Dal Pra, M. Marconi, B. Chakravarthy, J. F. Whitfield, and U. Armato, “Calcium-sensing receptor (CaSR) in human brain's pathophysiology: Roles in late-onset Alzheimer's disease (LOAD),” Current Pharmaceutical Biotechnology, vol. 10, no. 3, pp. 317–326, 2009.
- Y. Hashimoto, O. Tsuji, T. Niikura et al., “Involvement of c-Jun N-terminal kinase in amyloid precursor protein-mediated neuronal cell death,” Journal of Neurochemistry, vol. 84, no. 4, pp. 864–877, 2003.
- C. A. Marques, U. Keil, A. Bonert et al., “Neurotoxic mechanisms caused by the alzheimer's disease-linked Swedish amyloid precursor protein. Mutation oxidative stress, caspases, and the JNK pathway,” The Journal of Biological Chemistry, vol. 278, no. 30, pp. 28294–28302, 2003.
- B. Puig, T. Gómez-Isla, E. Ribé et al., “Expression of stress-activated kinases c-Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P), and tau hyperphosphorylation in neurites surrounding βA plaques in APP Tg2576 mice,” Neuropathology and Applied Neurobiology, vol. 30, no. 5, pp. 491–502, 2004.
- E. Tamagno, M. Parola, P. Bardini et al., “β-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways,” Journal of Neurochemistry, vol. 92, no. 3, pp. 628–636, 2005.
- C. Shen, Y. Chen, H. Liu et al., “Hydrogen peroxide promotes Aβ production through JNK-dependent activation of γ-secretase,” The Journal of Biological Chemistry, vol. 283, no. 25, pp. 17721–17730, 2008.
- A. Colombo, A. Bastone, C. Ploia et al., “JNK regulates APP cleavage and degradation in a model of Alzheimer's disease,” Neurobiology of Disease, vol. 33, no. 3, pp. 518–525, 2009.
- Z. Muresan and V. Muresan, “The amyloid-β precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration,” Molecular Biology of the Cell, vol. 18, no. 10, pp. 3835–3844, 2007.
- X. Fan, R. Subramaniam, M. F. Weiss, and V. M. Monnier, “Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor κB and intracellular reactive oxygen species formation,” Archives of Biochemistry and Biophysics, vol. 409, no. 2, pp. 274–286, 2003.
- A. Pal, I. Bhattacharya, K. Bhattacharya, C. Mandal, and M. Ray, “Methylglyoxal induced activation of murine peritoneal macrophages and surface markers of T lymphocytes in Sarcoma-180 bearing mice: Involvement of MAP kinase, NF-κβ signal transduction pathway,” Molecular Immunology, vol. 46, no. 10, pp. 2039–2044, 2009.
- S.-M. Huang, C.-L. Hsu, H.-C. Chuang, P.-H. Shih, C.-H. Wu, and G.-C. Yen, “Inhibitory effect of vanillic acid on methylglyoxal-mediated glycation in apoptotic Neuro-2A cells,” NeuroToxicology, vol. 29, no. 6, pp. 1016–1022, 2008.
- L. Heimfarth, S. O. Loureiro, P. Pierozan et al., “Methylglyoxal-induced cytotoxicity in neonatal rat brain: a role for oxidative stress and MAP kinases,” Metabolic Brain Disease, vol. 28, no. 3, pp. 429–438, 2013.
- P. Matafome, C. Sena, and R. Seica, “Methylglyoxal, obesity, and diabetes,” Endocrine, vol. 43, no. 3, pp. 472–484, 2013.
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