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Advanced glycation end products and neurodegenerative diseases: Mechanisms and perspective
Journal of the Neurological Sciences 317 (2012) 1–5
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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Review article
Advanced glycation end products and neurodegenerative diseases: Mechanisms and perspective Jinlong Li, Danian Liu, Ling Sun, Yunting Lu, Zhongling Zhang ⁎ Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
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Article history: Received 6 December 2011 Received in revised form 12 February 2012 Accepted 21 February 2012 Available online 11 March 2012 Keywords: Advanced glycation end products Amyloid β Tau α-Synuclein Neurodegenerative diseases Neurotoxicity
a b s t r a c t The age-related neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are characterized by the abnormal accumulation or aggregation of proteins. Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to sugars. The formation of AGEs promotes the deposition of proteins due to the protease resistant crosslinking between the peptides and proteins. Several proteins implicated in neurodegenerative diseases such as amyloid β, tau, α-synuclein, and prions are glycated and the extent of glycation is correlated with the pathologies of the patients. These data suggest that AGEs contribute to the development of neurodegenerative diseases. In this review we summarize recent advances on the investigation of the roles of AGEs in neurodegenerative diseases, with special focus on Alzheimer's and Parkinson's diseases. It is clear that AGEs modification triggers the abnormal deposition and accumulation of the modified proteins, which in turn sustain the local oxidative stress and inflammatory response, eventually leading to the pathological and clinical aspects of neurodegenerative diseases. Further characterization of the molecular mechanisms responsible for AGEs mediated neurotoxicity will provide important clues on the development of novel strategies for the prevention and treatment of neurodegenerative diseases. © 2012 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . 2. Protein glycation and the formation of AGEs 3. AGEs mediated signaling pathways . . . . 4. AGEs and Alzheimer's disease . . . . . . . 5. AGEs and Parkinson's disease . . . . . . . 6. Perspective . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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1. Introduction The last century has witnessed the significant increase in our life expectancy. Consequently, a variety of age related diseases have emerged, bringing new challenges to the society. Among them, neurodegenerative disorders are noteworthy due to their devastating nature and unsuccessful treatment options. A variety of central nervous system disorders are assorted as neurodegenerative disorders that include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and prion disease, which are characterized by the gradual and progressive loss of neural tissue or neurons and the deposition of misfolded or/and aggregated proteins ⁎ Corresponding author. Tel.: + 86 451 85555937. E-mail address: [email protected] (Z. Zhang). 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.02.018
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in the brain [1]. For example, the accumulation of amyloid βpeptide (Aβ) and tau protein is an important hallmark in AD, the accumulation of α-synuclein (α-syn) is a key pathological aspect of PD, while prion disease is characterized by the accumulation of a pathological form of the cellular prion protein (PrPc). An increasing body of evidence has demonstrated that oxidative stress plays an important role in the pathogenesis of neurodegenerative disorders [2]. Due to the high rate of oxygen consumption and glucose turnover, as well as elevated levels of the redox-active iron in certain regions, the brain is especially vulnerable to oxidative damage [3]. In addition, it is believed that the brain contains relatively low levels of antioxidants such as glutathione and vitamin E and antioxidant enzymes including GSH peroxidase, catalase and superoxide dismutase [4]. All these factors lead to high oxidative stress in the brain, contributing to the pathogenesis of neurodegenerative diseases.
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The formation of advanced glycation end products (AGEs) is known as an important consequence of oxidative stress in the brain. Moreover, the formation of AGEs could induce oxidative stress, forming a positive feedback loop to augment oxidative damage in the brain [5]. Therefore, AGEs are recognized to play an important role in the development of AD and other neurodegenerative diseases [6]. In this review, we will describe an overview of the generation of AGEs focusing on the processes of non-enzymatic glycation, and then present the current evidence supporting the role of AGEs in the development of neurodegenerative diseases. Finally, we will discuss the potential utilization of AGEs as biomarkers or therapeutic targets for neurodegenerative diseases. 2. Protein glycation and the formation of AGEs A sugar aldehyde or ketone can react with the amino groups of proteins in a non-enzymatic reaction, giving rise to a Schiff base. This posttranslational modification of proteins is termed as “protein glycation”, “non-enzymatic glycosylation”, or “Maillard reaction”, which is reversible and occurs until reaching equilibrium. However, the Schiff base is slowly rearranged giving the so-called Amadori product that is fructosamine. This is the early glycation process and the compounds formed are considered early glycation adducts. Furthermore, the early adducts undergo a further rearrangement and eventually dehydration, condensation, fragmentation, oxidation and cyclization reactions, giving rise to compounds bound irreversibly, the so-called AGEs (Fig. 1) [7]. Notably, the latter reactions of the adducts could be accelerated by transition metals such as iron and copper which oxidize the protein-bound Amadori products. The formation of AGEs is irreversible and leads to the deposition of proteins due to the protease resistant crosslinking between the AGEcontaining peptide fragments and proteins. In addition, AGEs are formed through alternative glycolytic pathways with dicarbonyl compounds that include methylglyoxal (MG), glyoxal and 3-deoxyglucosone (3-DG). These compounds are also called α-oxoaldehydes and are formed by glycation, degradation of glycolytic intermediates as well as lipid peroxidation. MG is mainly formed by the non-enzymatic β-elimination of the phosphate group from the triose phosphates derived from glycolysis [8]. Glucose is known to be present at high levels in the blood but it has a low specific glycation activity. In contrast, MG is present at low levels in the circulating blood but has a high specific glycation activity. Therefore, MG is considered as the most reactive glycation agent in vivo [9–11]. Glyoxal can be formed from glucose by retroaldol condensation activated by deprotonation of the 2- or 3-hydroxy groups. Glyoxal is also formed in the lipid peroxidation. In addition, autoxidative processes could stimulate the formation of glyoxal via hydroxyl radical-mediated acetal proton abstraction from glucopyranose and β-elimination reactions [12]. 3-DG is formed by an initial activation step, deprotonation of carbon-2: redistribution of the electron density between carbon-1 and carbon-2 leads to the formation of the 1-diol, or redistribution of the
electronic density leads to the 2,3-enol and thereby 3-DG. 3-DG is also a highly reactive carbonyl compound. The chemical structures of the main AGEs and the main pathways for the formation of these AGEs are summarized in Fig. 2 [7]. Fortunately, several enzyme systems exist in the human body to antagonize AGEs formation from precursors MG, glyoxal and 3-DG. MG and glyoxal are subject to the detoxification effects of several enzymes: the NADPH-dependent aldose reductase, aldehyde dehydrogenase, 2-oxoaldehyde dehydrogenase and the glyoxalase system [13]. Notably, MG is one of the substrates of the glyoxalase system that functions to protect cells from α-oxoaldehyde mediated AGE formation. The glyoxalase system consists of two enzymes, glyoxalase I and glyoxalase II, and a catalytic amount of glutathione, which work together to detoxify α-oxoaldehydes in the cells. Nevertheless, upon oxidative stress, thiol concentration is reduced. Consequently, αoxoaldehydes could not be detoxified and their accumulation promotes the formation of α-oxoaldehydes mediated AGEs [13]. On the other hand, a reducing enzyme system functions to detoxify 3-DG to 3-deoxyfructose which is then excreted through the urine [14]. 3. AGEs mediated signaling pathways As the ligand, AGEs are known to bind to the cell surface receptor RAGE (the receptor for advanced glycation end products) to initiate a series of physiological and pathological processes [15]. RAGE is a member of the immunoglobulin superfamily of cell surface molecules, i.e., type-I transmembrane protein. RAGE is composed of an extracellular domain containing 344 amino acids, a transmembrane domain containing 19 residues, and a cytoplasmic domain containing 43 amino acids [16]. The large extracellular domain of RAGE contains an N-terminal signal sequence of 22 amino acids and three immunoglobulin (Ig)-like regions, which define RAGE as a member of the immunoglobulin superfamily. These Ig-like regions include one “V”-type domain (IgV sequence from residue 41 to residue 126) followed by two “C”-type domains (IgC sequence from residue 127 to residue 234 and IgC′ from residue 235 to residue 344). The “V”-type domain confers ligand binding ability. Notably, the V-type domain contains two putative N-glycosylation sites and the glycosylation of these sites has been shown to affect the binding of RAGE to its ligands [17]. In contrast, the short cytoplasmic domain is critical for signaling downstream of receptor–ligand interaction [18]. Although AGEs are important ligands of RAGE, RAGE also interacts with a diversity of other ligands, including β-sheet fibrils, several members of the S100 protein family (S100B, S100P, S100A4, S100A6, S100A8/9, S100A11–13), high mobility group box-1 (HMGB1), and prions [19]. The engagement of RAGE by its ligands has been reported to trigger multiple intracellular signaling pathways. Typically, RAGE induces the activation of the immune/inflammatory-associated transcription factor NF-kB. Interestingly, the human RAGE promoter contains two NF-kB responsive elements that form a positive feedback loop such that RAGE is upregulated where its ligands are present [20]. In
Fig. 1. The process of protein glycation by glucose.
J. Li et al. / Journal of the Neurological Sciences 317 (2012) 1–5
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Fig. 2. The formation of AGEs. A. The chemical structures of the main AGEs, B. The main pathways of the formation of AGEs. CML: Nε-carboxymethyllysine; CEL: Nεcarboxyethyllysine; GOLD: glyoxal-lysine dimer; MOLD: methyglyoxal-lysine dimer; DOLD: deoxyglucosone-lysine dimer; GLAP: glyceraldehyde-derived pyridinium compound. Modified from Ref. [7].
addition, RAGE induces the activation of signaling pathways such as nuclear factor of activated T-cells (NF-AT) [21], mitogen-activated protein kinase and extracellular signal-regulated kinase signaling [22], cAMP response element-binding factor [23], and c-Jun Nterminal kinase signaling [24]. The diversity of signaling cascades identified in RAGE-mediated cellular signaling suggests that there is no any single mode of RAGE activation by different RAGE ligands and calls for our further investigation. Moreover, the proximal signaling events directly downstream of the receptor remain largely unknown. The identification and characterization of direct binding partners of the cytoplasmic domain of RAGE may provide a clue. In this aspect, Hudson et al. recently reported that diaphanous-1, a target of the small GTPase that regulates actin dynamics, could directly bind RAGE cytoplasmic domain and thus mediate ligand stimulated cellular migration through downstream activation of Rac1 and Cdc42 [25]. We expect that more binding partners of RAGE cytoplasmic domain will be identified in the near future, which will help us understand the complete scenario of downstream signal transduction upon RAGE activation.
4. AGEs and Alzheimer's disease Alzheimer's disease (AD) is the most prevalent type of dementia in the elderly. AD is characterized by a gradual and progressive decline in the cognitive and functional abilities of the affected individual [26]. The formation of amyloid plaques and intracellular neurofibrillary tangles is one of several processes likely causing loss of synapses and neuronal cell death, which may contribute to the decline in the cognitive and functional abilities in AD patients [27]. The aggregation and deposition of proteins derived from AGE modification and the resulting cross-linking have been observed in both plaques and tangles. For example, AGEs accumulation has been shown in senile plaques in different cortical areas, in primitive plaques, coronas of classic plaques and some glial cells of AD brain [28]. Moreover, the polymerization of β-amyloid, the major component of senile plaques, was shown to be significantly accelerated by AGEs mediated protein cross-linking [29]. More recent data showed that amyloid precursor protein (APP) expression was up-regulated by AGEs in vitro and in vivo, leading to an increased β-amyloid level. These effects mediated by AGEs could be blocked by the pretreatment of the cells with an ROS inhibitor (N-acetyl-L-cysteine) [30]. These results may help elucidate a new mechanism by which AGEs participate in AD development and reveal AGEs as an important risk factor in the pathogenesis of AD.
ApoE4 is known as an important susceptibility gene for AD [31]. Interestingly, ApoE was shown to exhibit specific binding activity to AGEs, with the dimeric form of ApoE binding better than the monomeric form. In particular, the ApoE4 isoform exhibited a 3-fold greater binding activity to AGEs than the ApoE3 isoform [32]. This study suggests that ApoE may promote the aggregate formation in the AD brain by binding to AGEs modified plaque components, which may explain why ApoE4 contributes to increased risk of AD. Neurofibrillary tangles (NFTs) are most commonly known as a primary marker of AD. NFTs are the aggregates of hyperphosphorylated microtubuli associated tau protein. Notably, tau protein from AD was glycated at its tubulin binding site, and the glycated tau was able to induce oxidative stress [33]. Therefore, AGEs contribute to the formation and toxicity of NFTs. Interestingly, a very recent study reported that AGEs could induce tau protein hyperphosphorylation and impair synapse and memory in rats likely through RAGE mediated GSK-3 activation [34]. Taken together, these data suggest that in addition to the well established role of AGEs in β-amyloid formation and aggregation, AGEs participate in the formation of NFTs. These results also help explain why AGEs are crucial pathological factors for AD given that the accumulation of β-amyloid and hyperphosphorylated tau is regarded as the hallmark lesion of AD.
5. AGEs and Parkinson's disease As the second most common progressive neurodegenerative disease, PD affects about 1.5% of the elderly over 60 years old [35]. The main symptoms of PD include tremor or shaking, stiff muscles and achiness, limited movement, and difficulty with walking (gait disturbance) and balance (postural instability) [36]. PD is characterized by neuronal cell loss in the Substantia Nigra (SN) pars compacta and the accumulation of intracellular proteinaceous inclusions such as Lewy bodies and neuromelanin is regarded as the pathological hallmark of PD [37]. Lewy bodies predominantly contain neurofilament proteins including α-synuclein (α-syn). Under physiological conditions, α-syn exhibits a natively unfolded conformation. However, under pathological situations, it could form aggregates or oligomers which are believed as the most cytotoxic forms [38]. α-Syn is known to be subject to several post-translational modifications such as oxidation, phosphorylation and glycation which may promote the aggregation process [38]. Notably, α-syn is a lysine-rich protein and contains 15 residues that are putative glycation targets. Indeed, recent studies showed that AGEs induce the aggregation of α-syn in vitro [39,40]. Moreover, α-syn is rapidly glycated in the presence of
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D-ribose generating molten globule-like aggregations which cause cell oxidative stress and result in high cytotoxicity [41]. In vivo, histochemical analysis demonstrated that AGE and RAGE levels were increased in the frontal cortex of PD patients compared to controls [42]. This is consistent with early study which suggested that glycoxidation and oxidative stress are important pathogenic factors in diseases characterized by Lewy body formation, and crosslinking by AGEs contributes to the formation of protein deposits [43]. Based on these data we could speculate that AGEs promote the aggregation of α-syn and the formation of Lewy bodies, thus contributing to the pathogenesis of PD.
6. Perspective In this review we attempted to summarize advances on the investigation of the roles of AGEs in neurodegenerative diseases, with special focus on AD and PD. In fact AGEs are also implicated in the pathogenesis of other neurodegenerative diseases such as Huntington's diseases, amyotrophic lateral sclerosis (ALS), familial amyloid polyneuropathy (FAP) and Creutzfeld–Jakob disease (CJD) [44–47]. It is clear that AGEs modification triggers the abnormal deposition and accumulation of the modified proteins, leading to their increased protease resistance and insolubility, which in turn sustain the local oxidative stress and inflammatory response. Consequently, the cells become dysfunctional and even dead, and the pathological and clinical aspects of neurodegenerative diseases present. Given the crucial role of AGEs in neurodegenerative diseases, it is important to further characterize the molecular mechanisms responsible for AGEs mediated neurotoxicity. This will provide important clues on the development of novel strategies for the prevention and treatment of neurodegenerative diseases. Fortunately, recent innovations in technology greatly facilitate our investigation. For example, recently we employed 2-D Fluorescence Difference Gel Electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry to identify proteins involved in MG mediated neurotoxicity. Proteomics analysis revealed several candidates such as actin, immunoglobulin lambda light chain and protein phosphatase 2, which have been implicated in AD pathogenesis [48]. These results suggest that multiple pathways are possibly involved in MG-induced neuron death, which represent potential therapeutic targets. Notably, a recently completed 12-year follow-up study confirmed that higher plasma levels of AGEs are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes [49]. Large scale and long term retrospective studies are required to evaluate the potential of AGEs as reliable biomarkers of neurodegenerative diseases, although it is proposed that higher AGE concentrations in brain tissue and in cerebrospinal fluid are able to distinguish between normal aging and AD [50]. Once confirmed, we could utilize AGEs for the early diagnosis of neurodegenerative diseases. On the other hand, it is known that oxidative stress and AGEs initiate a positive feedback loop in human body including the brain, where AGEs promote the development of normal age-related changes into neurodegeneration. Therefore, targeted pharmacological interventions utilizing AGEs inhibitors, antioxidants, inflammatory inhibitors, RAGE antagonists, RAGE antibodies or decoy receptor soluble RAGE will emerge as promising strategies for the prevention and therapy of neurodegenerative diseases.
Conflict of interest The authors declare that there are no any financial or personal relationships with other people or organizations that could inappropriately influence this work.
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Review article
Advanced glycation end products and neurodegenerative diseases: Mechanisms and perspective Jinlong Li, Danian Liu, Ling Sun, Yunting Lu, Zhongling Zhang ⁎ Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
a r t i c l e
i n f o
Article history: Received 6 December 2011 Received in revised form 12 February 2012 Accepted 21 February 2012 Available online 11 March 2012 Keywords: Advanced glycation end products Amyloid β Tau α-Synuclein Neurodegenerative diseases Neurotoxicity
a b s t r a c t The age-related neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are characterized by the abnormal accumulation or aggregation of proteins. Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to sugars. The formation of AGEs promotes the deposition of proteins due to the protease resistant crosslinking between the peptides and proteins. Several proteins implicated in neurodegenerative diseases such as amyloid β, tau, α-synuclein, and prions are glycated and the extent of glycation is correlated with the pathologies of the patients. These data suggest that AGEs contribute to the development of neurodegenerative diseases. In this review we summarize recent advances on the investigation of the roles of AGEs in neurodegenerative diseases, with special focus on Alzheimer's and Parkinson's diseases. It is clear that AGEs modification triggers the abnormal deposition and accumulation of the modified proteins, which in turn sustain the local oxidative stress and inflammatory response, eventually leading to the pathological and clinical aspects of neurodegenerative diseases. Further characterization of the molecular mechanisms responsible for AGEs mediated neurotoxicity will provide important clues on the development of novel strategies for the prevention and treatment of neurodegenerative diseases. © 2012 Elsevier B.V. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . 2. Protein glycation and the formation of AGEs 3. AGEs mediated signaling pathways . . . . 4. AGEs and Alzheimer's disease . . . . . . . 5. AGEs and Parkinson's disease . . . . . . . 6. Perspective . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . .
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1. Introduction The last century has witnessed the significant increase in our life expectancy. Consequently, a variety of age related diseases have emerged, bringing new challenges to the society. Among them, neurodegenerative disorders are noteworthy due to their devastating nature and unsuccessful treatment options. A variety of central nervous system disorders are assorted as neurodegenerative disorders that include Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and prion disease, which are characterized by the gradual and progressive loss of neural tissue or neurons and the deposition of misfolded or/and aggregated proteins ⁎ Corresponding author. Tel.: + 86 451 85555937. E-mail address: [email protected] (Z. Zhang). 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.02.018
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in the brain [1]. For example, the accumulation of amyloid βpeptide (Aβ) and tau protein is an important hallmark in AD, the accumulation of α-synuclein (α-syn) is a key pathological aspect of PD, while prion disease is characterized by the accumulation of a pathological form of the cellular prion protein (PrPc). An increasing body of evidence has demonstrated that oxidative stress plays an important role in the pathogenesis of neurodegenerative disorders [2]. Due to the high rate of oxygen consumption and glucose turnover, as well as elevated levels of the redox-active iron in certain regions, the brain is especially vulnerable to oxidative damage [3]. In addition, it is believed that the brain contains relatively low levels of antioxidants such as glutathione and vitamin E and antioxidant enzymes including GSH peroxidase, catalase and superoxide dismutase [4]. All these factors lead to high oxidative stress in the brain, contributing to the pathogenesis of neurodegenerative diseases.
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The formation of advanced glycation end products (AGEs) is known as an important consequence of oxidative stress in the brain. Moreover, the formation of AGEs could induce oxidative stress, forming a positive feedback loop to augment oxidative damage in the brain [5]. Therefore, AGEs are recognized to play an important role in the development of AD and other neurodegenerative diseases [6]. In this review, we will describe an overview of the generation of AGEs focusing on the processes of non-enzymatic glycation, and then present the current evidence supporting the role of AGEs in the development of neurodegenerative diseases. Finally, we will discuss the potential utilization of AGEs as biomarkers or therapeutic targets for neurodegenerative diseases. 2. Protein glycation and the formation of AGEs A sugar aldehyde or ketone can react with the amino groups of proteins in a non-enzymatic reaction, giving rise to a Schiff base. This posttranslational modification of proteins is termed as “protein glycation”, “non-enzymatic glycosylation”, or “Maillard reaction”, which is reversible and occurs until reaching equilibrium. However, the Schiff base is slowly rearranged giving the so-called Amadori product that is fructosamine. This is the early glycation process and the compounds formed are considered early glycation adducts. Furthermore, the early adducts undergo a further rearrangement and eventually dehydration, condensation, fragmentation, oxidation and cyclization reactions, giving rise to compounds bound irreversibly, the so-called AGEs (Fig. 1) [7]. Notably, the latter reactions of the adducts could be accelerated by transition metals such as iron and copper which oxidize the protein-bound Amadori products. The formation of AGEs is irreversible and leads to the deposition of proteins due to the protease resistant crosslinking between the AGEcontaining peptide fragments and proteins. In addition, AGEs are formed through alternative glycolytic pathways with dicarbonyl compounds that include methylglyoxal (MG), glyoxal and 3-deoxyglucosone (3-DG). These compounds are also called α-oxoaldehydes and are formed by glycation, degradation of glycolytic intermediates as well as lipid peroxidation. MG is mainly formed by the non-enzymatic β-elimination of the phosphate group from the triose phosphates derived from glycolysis [8]. Glucose is known to be present at high levels in the blood but it has a low specific glycation activity. In contrast, MG is present at low levels in the circulating blood but has a high specific glycation activity. Therefore, MG is considered as the most reactive glycation agent in vivo [9–11]. Glyoxal can be formed from glucose by retroaldol condensation activated by deprotonation of the 2- or 3-hydroxy groups. Glyoxal is also formed in the lipid peroxidation. In addition, autoxidative processes could stimulate the formation of glyoxal via hydroxyl radical-mediated acetal proton abstraction from glucopyranose and β-elimination reactions [12]. 3-DG is formed by an initial activation step, deprotonation of carbon-2: redistribution of the electron density between carbon-1 and carbon-2 leads to the formation of the 1-diol, or redistribution of the
electronic density leads to the 2,3-enol and thereby 3-DG. 3-DG is also a highly reactive carbonyl compound. The chemical structures of the main AGEs and the main pathways for the formation of these AGEs are summarized in Fig. 2 [7]. Fortunately, several enzyme systems exist in the human body to antagonize AGEs formation from precursors MG, glyoxal and 3-DG. MG and glyoxal are subject to the detoxification effects of several enzymes: the NADPH-dependent aldose reductase, aldehyde dehydrogenase, 2-oxoaldehyde dehydrogenase and the glyoxalase system [13]. Notably, MG is one of the substrates of the glyoxalase system that functions to protect cells from α-oxoaldehyde mediated AGE formation. The glyoxalase system consists of two enzymes, glyoxalase I and glyoxalase II, and a catalytic amount of glutathione, which work together to detoxify α-oxoaldehydes in the cells. Nevertheless, upon oxidative stress, thiol concentration is reduced. Consequently, αoxoaldehydes could not be detoxified and their accumulation promotes the formation of α-oxoaldehydes mediated AGEs [13]. On the other hand, a reducing enzyme system functions to detoxify 3-DG to 3-deoxyfructose which is then excreted through the urine [14]. 3. AGEs mediated signaling pathways As the ligand, AGEs are known to bind to the cell surface receptor RAGE (the receptor for advanced glycation end products) to initiate a series of physiological and pathological processes [15]. RAGE is a member of the immunoglobulin superfamily of cell surface molecules, i.e., type-I transmembrane protein. RAGE is composed of an extracellular domain containing 344 amino acids, a transmembrane domain containing 19 residues, and a cytoplasmic domain containing 43 amino acids [16]. The large extracellular domain of RAGE contains an N-terminal signal sequence of 22 amino acids and three immunoglobulin (Ig)-like regions, which define RAGE as a member of the immunoglobulin superfamily. These Ig-like regions include one “V”-type domain (IgV sequence from residue 41 to residue 126) followed by two “C”-type domains (IgC sequence from residue 127 to residue 234 and IgC′ from residue 235 to residue 344). The “V”-type domain confers ligand binding ability. Notably, the V-type domain contains two putative N-glycosylation sites and the glycosylation of these sites has been shown to affect the binding of RAGE to its ligands [17]. In contrast, the short cytoplasmic domain is critical for signaling downstream of receptor–ligand interaction [18]. Although AGEs are important ligands of RAGE, RAGE also interacts with a diversity of other ligands, including β-sheet fibrils, several members of the S100 protein family (S100B, S100P, S100A4, S100A6, S100A8/9, S100A11–13), high mobility group box-1 (HMGB1), and prions [19]. The engagement of RAGE by its ligands has been reported to trigger multiple intracellular signaling pathways. Typically, RAGE induces the activation of the immune/inflammatory-associated transcription factor NF-kB. Interestingly, the human RAGE promoter contains two NF-kB responsive elements that form a positive feedback loop such that RAGE is upregulated where its ligands are present [20]. In
Fig. 1. The process of protein glycation by glucose.
J. Li et al. / Journal of the Neurological Sciences 317 (2012) 1–5
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Fig. 2. The formation of AGEs. A. The chemical structures of the main AGEs, B. The main pathways of the formation of AGEs. CML: Nε-carboxymethyllysine; CEL: Nεcarboxyethyllysine; GOLD: glyoxal-lysine dimer; MOLD: methyglyoxal-lysine dimer; DOLD: deoxyglucosone-lysine dimer; GLAP: glyceraldehyde-derived pyridinium compound. Modified from Ref. [7].
addition, RAGE induces the activation of signaling pathways such as nuclear factor of activated T-cells (NF-AT) [21], mitogen-activated protein kinase and extracellular signal-regulated kinase signaling [22], cAMP response element-binding factor [23], and c-Jun Nterminal kinase signaling [24]. The diversity of signaling cascades identified in RAGE-mediated cellular signaling suggests that there is no any single mode of RAGE activation by different RAGE ligands and calls for our further investigation. Moreover, the proximal signaling events directly downstream of the receptor remain largely unknown. The identification and characterization of direct binding partners of the cytoplasmic domain of RAGE may provide a clue. In this aspect, Hudson et al. recently reported that diaphanous-1, a target of the small GTPase that regulates actin dynamics, could directly bind RAGE cytoplasmic domain and thus mediate ligand stimulated cellular migration through downstream activation of Rac1 and Cdc42 [25]. We expect that more binding partners of RAGE cytoplasmic domain will be identified in the near future, which will help us understand the complete scenario of downstream signal transduction upon RAGE activation.
4. AGEs and Alzheimer's disease Alzheimer's disease (AD) is the most prevalent type of dementia in the elderly. AD is characterized by a gradual and progressive decline in the cognitive and functional abilities of the affected individual [26]. The formation of amyloid plaques and intracellular neurofibrillary tangles is one of several processes likely causing loss of synapses and neuronal cell death, which may contribute to the decline in the cognitive and functional abilities in AD patients [27]. The aggregation and deposition of proteins derived from AGE modification and the resulting cross-linking have been observed in both plaques and tangles. For example, AGEs accumulation has been shown in senile plaques in different cortical areas, in primitive plaques, coronas of classic plaques and some glial cells of AD brain [28]. Moreover, the polymerization of β-amyloid, the major component of senile plaques, was shown to be significantly accelerated by AGEs mediated protein cross-linking [29]. More recent data showed that amyloid precursor protein (APP) expression was up-regulated by AGEs in vitro and in vivo, leading to an increased β-amyloid level. These effects mediated by AGEs could be blocked by the pretreatment of the cells with an ROS inhibitor (N-acetyl-L-cysteine) [30]. These results may help elucidate a new mechanism by which AGEs participate in AD development and reveal AGEs as an important risk factor in the pathogenesis of AD.
ApoE4 is known as an important susceptibility gene for AD [31]. Interestingly, ApoE was shown to exhibit specific binding activity to AGEs, with the dimeric form of ApoE binding better than the monomeric form. In particular, the ApoE4 isoform exhibited a 3-fold greater binding activity to AGEs than the ApoE3 isoform [32]. This study suggests that ApoE may promote the aggregate formation in the AD brain by binding to AGEs modified plaque components, which may explain why ApoE4 contributes to increased risk of AD. Neurofibrillary tangles (NFTs) are most commonly known as a primary marker of AD. NFTs are the aggregates of hyperphosphorylated microtubuli associated tau protein. Notably, tau protein from AD was glycated at its tubulin binding site, and the glycated tau was able to induce oxidative stress [33]. Therefore, AGEs contribute to the formation and toxicity of NFTs. Interestingly, a very recent study reported that AGEs could induce tau protein hyperphosphorylation and impair synapse and memory in rats likely through RAGE mediated GSK-3 activation [34]. Taken together, these data suggest that in addition to the well established role of AGEs in β-amyloid formation and aggregation, AGEs participate in the formation of NFTs. These results also help explain why AGEs are crucial pathological factors for AD given that the accumulation of β-amyloid and hyperphosphorylated tau is regarded as the hallmark lesion of AD.
5. AGEs and Parkinson's disease As the second most common progressive neurodegenerative disease, PD affects about 1.5% of the elderly over 60 years old [35]. The main symptoms of PD include tremor or shaking, stiff muscles and achiness, limited movement, and difficulty with walking (gait disturbance) and balance (postural instability) [36]. PD is characterized by neuronal cell loss in the Substantia Nigra (SN) pars compacta and the accumulation of intracellular proteinaceous inclusions such as Lewy bodies and neuromelanin is regarded as the pathological hallmark of PD [37]. Lewy bodies predominantly contain neurofilament proteins including α-synuclein (α-syn). Under physiological conditions, α-syn exhibits a natively unfolded conformation. However, under pathological situations, it could form aggregates or oligomers which are believed as the most cytotoxic forms [38]. α-Syn is known to be subject to several post-translational modifications such as oxidation, phosphorylation and glycation which may promote the aggregation process [38]. Notably, α-syn is a lysine-rich protein and contains 15 residues that are putative glycation targets. Indeed, recent studies showed that AGEs induce the aggregation of α-syn in vitro [39,40]. Moreover, α-syn is rapidly glycated in the presence of
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D-ribose generating molten globule-like aggregations which cause cell oxidative stress and result in high cytotoxicity [41]. In vivo, histochemical analysis demonstrated that AGE and RAGE levels were increased in the frontal cortex of PD patients compared to controls [42]. This is consistent with early study which suggested that glycoxidation and oxidative stress are important pathogenic factors in diseases characterized by Lewy body formation, and crosslinking by AGEs contributes to the formation of protein deposits [43]. Based on these data we could speculate that AGEs promote the aggregation of α-syn and the formation of Lewy bodies, thus contributing to the pathogenesis of PD.
6. Perspective In this review we attempted to summarize advances on the investigation of the roles of AGEs in neurodegenerative diseases, with special focus on AD and PD. In fact AGEs are also implicated in the pathogenesis of other neurodegenerative diseases such as Huntington's diseases, amyotrophic lateral sclerosis (ALS), familial amyloid polyneuropathy (FAP) and Creutzfeld–Jakob disease (CJD) [44–47]. It is clear that AGEs modification triggers the abnormal deposition and accumulation of the modified proteins, leading to their increased protease resistance and insolubility, which in turn sustain the local oxidative stress and inflammatory response. Consequently, the cells become dysfunctional and even dead, and the pathological and clinical aspects of neurodegenerative diseases present. Given the crucial role of AGEs in neurodegenerative diseases, it is important to further characterize the molecular mechanisms responsible for AGEs mediated neurotoxicity. This will provide important clues on the development of novel strategies for the prevention and treatment of neurodegenerative diseases. Fortunately, recent innovations in technology greatly facilitate our investigation. For example, recently we employed 2-D Fluorescence Difference Gel Electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry to identify proteins involved in MG mediated neurotoxicity. Proteomics analysis revealed several candidates such as actin, immunoglobulin lambda light chain and protein phosphatase 2, which have been implicated in AD pathogenesis [48]. These results suggest that multiple pathways are possibly involved in MG-induced neuron death, which represent potential therapeutic targets. Notably, a recently completed 12-year follow-up study confirmed that higher plasma levels of AGEs are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes [49]. Large scale and long term retrospective studies are required to evaluate the potential of AGEs as reliable biomarkers of neurodegenerative diseases, although it is proposed that higher AGE concentrations in brain tissue and in cerebrospinal fluid are able to distinguish between normal aging and AD [50]. Once confirmed, we could utilize AGEs for the early diagnosis of neurodegenerative diseases. On the other hand, it is known that oxidative stress and AGEs initiate a positive feedback loop in human body including the brain, where AGEs promote the development of normal age-related changes into neurodegeneration. Therefore, targeted pharmacological interventions utilizing AGEs inhibitors, antioxidants, inflammatory inhibitors, RAGE antagonists, RAGE antibodies or decoy receptor soluble RAGE will emerge as promising strategies for the prevention and therapy of neurodegenerative diseases.
Conflict of interest The authors declare that there are no any financial or personal relationships with other people or organizations that could inappropriately influence this work.
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