Involvement of Maillard Reactions in Alzheimer Disease

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V. PRAKASH REDDYa,*, MARK E. OBRENOVICHb, CRAIG S. ATWOODb, GEORGE PERRYb and MARK A. SMITH†b. aDepartment of Chemistry, University of ...
Neurotoxicity Research, 2002 Vol. 4 (3), pp. 191–209

Involvement of Maillard Reactions in Alzheimer Disease V. PRAKASH REDDYa,*, MARK E. OBRENOVICHb, CRAIG S. ATWOODb, GEORGE PERRYb and MARK A. SMITH†b a

Department of Chemistry, University of Missouri-Rolla, Rolla, MO 65409, USA; bInstitute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA (Received 1 November 2001; Revised 10 December 2001; In final form 10 December 2001)

Maillard reactions have been explored by food chemists for many years. It is only recently that the advanced glycation end products (AGEs), the end products of the Maillard reaction, have been detected in a wide variety of diseases such as diabetes, atherosclerosis, cataractogenesis, Parkinson disease and Alzheimer disease (AD). In this review, we discuss the chemistry and biochemistry of AGE-related crosslinks such as pyrraline, pentosidine, carboxymethyllysine (CML), crosslines, imidazolidinones, and dilysine crosslinks (GOLD and MOLD), as well as their possible involvement in neurodegenerative conditions. Pentosidine and CML are found in elevated amounts in the major lesions of the AD brain. Glycation is also implicated in the formation of the paired helical filaments (PHF), a component of the neurofibrillary tangles (NFTs). Amyloid-b peptide and proteins of the cerebrospinal fluid are also glycated in patients with AD. In order to ameliorate the effects of AGEs on AD pathology, various inhibitors of AGEs have been increasingly explored. It is hoped that understanding of the mechanism of the AGEs formation and their role in the neurodegeneration will result in novel therapeutics for neuroprotection. Keywords: Advanced glycation end products; Alzheimer disease; Amyloid-b; Glycation; Maillard reaction; Neurodegeneration

INTRODUCTION The reactions of reducing sugars with amino groups (derived from amino acids, amines, or proteins) give a variety of reaction products through the intermediacy of a complex series of reactions, which are collectively known as Maillard reaction. Under physiological conditions, the initial reactions of the

carbonyl groups of the reducing sugars with the free amino groups of the proteins, especially those proteins which contain lysine, tryptophan, histidine, and arginine residues, give Schiff bases, which undergo Amadori rearrangements (Munch et al., 1999). This stage of the reaction is usually called Glycation (or Glycosylation). Further oxidative degradations of the glycated proteins (glycoxidations) give reactive, low molecular weight adicarbonyl compounds, which may further react with proteins to give crosslinked proteins. The latter crosslinks are generally known as advanced glycation end products (AGEs). Many AGEs are fluorescent and intensely colored compounds (typical excitation at 330 nm and emission at 400 nm) (Ledl and Schleicher, 1990; Vlassara et al., 1994; Brownlee, 1995; Thorpe and Baynes, 1996). The Maillard reactions are also called as “browning reactions” as they lead to a multitude of “browning” products that enhance the flavor and aroma of the cooked foods. Some Maillard products are known to have strong antioxidant properties in vitro (Devchand and De Muelenaere, 1996; Mastrocola and Munari, 2000). However, in the presence of redox active transition metal ions, the Maillard products act as pro-oxidants (Loske et al., 2000). The AGEs formed by the nonenzymatic glycations and glycoxidations contribute to fluorescence and insolubility to tissue proteins in age-related diseases, such as diabetes and atherosclerosis. They are implicated in pathophysiological changes associated with a number of diseases such as diabetes, atherosclerosis, uremia, end-stage renal disease, and, more recently, in neurodegenerative disorders.

*Corresponding author. Tel.: þ1-573-341-4768. Fax: þ1-573-341-6033. E-mail: [email protected] † Tel.: þ1-216-368-3670. Fax: þ1-216-368-8964; e-mail: [email protected] ISSN 1029-8428 print/ISSN 1476-3524 online q 2002 Taylor & Francis Ltd DOI: 10.1080/1029840290007321

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The latter include Huntington disease, Parkinson disease, amyotrophic lateral sclerosis (ALS) and Alzheimer disease (AD), all of which involve the formation of the abnormal forms of the protein aggregates. The accumulation of AGEs not only leads to their deposition in tissues, but also feedsforward the activation process of oxidative stress. The AGEs and oxidative stress may collectively contribute to the pathology associated with AD and other neurodegeneration related diseases (Durany et al., 1999; Bence et al., 2001). Posttranslational modifications induced by AGEs are, in part, responsible for the formation of extracellular amyloid-b deposits (senile plaques), intracellular tprotein aggregates (NFTs), and Hirano bodies in cases of AD (Munch et al., 1998a). Although the pathological implications of the AGEs are not well established (Munch et al., 1998b), it is well accepted that they act as markers of the advancement of the pathophysiological conditions, i.e. the formation of AGEs increases with increasing age and progression of pathology. The impact of AGEs in AD has been recently demonstrated. Smith, Perry and coworkers (Smith et al., 1994a,b; 1995a), as well as Cerami and coworkers, and others, have investigated the relationship between AGEs and the onset of AD (Vitek et al., 1994; Tabaton et al., 1997). They found that antibodies specific to AGEs such as carboxymethyllysine (CML), pyrraline and pentosidine, immunocytochemically label proteins present in NFT and senile plaques. The synthetic amyloid plaques are glycated in vitro, which can be immunocytochemically detected. AGEs also induce neurotoxicity in cultured cortical neurons in a dose dependent manner (Takeuchi et al., 2000). AGE immunoreactivity has also been demonstrated in the canine brains, whose pattern of AGE distribution is comparable to that of humans (Weber et al., 1998). Intracellular AGEs may render cytoskeletal proteins insoluble by cross-linking them and inhibiting normal cellular function. This eventually plays a role in the neuronal dysfunction characteristic of AD, by inhibiting cellular functions like transport processes. Additionally, extracellular AGEs also exert chronic oxidative stress on neurons, either directly, or indirectly by the production of reactive nitrogen and oxygen species through the activation of glial cells (Dukic-Stefanovic et al., 2001). Neurotoxic free radical species superoxide and nitric oxide (NO), and cytokines such as tumor necrosis factor-a (TNFa) are produced by glial cells in response to these AGEs. The extracellular AGEs that accumulate on long-lived protein deposits, especially the senile plaques, exert chronic oxidative stress on neurons. The combined approach using AGE inhibitors, antioxidants, and anti-inflammatory substances may prove to be effective in the treatment of AGE induced pathophysiological conditions.

In view of the enormous importance of AGEs, as markers and as the possible causative factors to the onset of AD, it would be instructive to understand the chemical nature of the various AGEs and the mechanisms of their formation and action. The broad scope of the Maillard reaction is well reviewed (Smith et al., 1994a; Baynes and Thorpe, 1999; Ulrich and Cerami, 2001). Here, we include only the recent developments relevant to neurodegenerative diseases, focusing on AD. We will discuss the chemistry and biochemistry of various AGEs, their implications in AD, and potential AGE inhibitors. We also discuss some AGEs, which have not yet been implicated in neurodegenerative disorders but are likely to be involved.

AMADORI REARRANGEMENTS AND AGE FORMATION The Maillard (browning) reactions are initiated by the reaction of the free amino groups of the amino acids, peptides, or proteins with the carbonyl groups of the reducing sugars giving the Schiff bases. The latter are formed reversibly, and under physiological conditions, undergo further rearrangements, called Amadori rearrangements. The Schiff bases and Amadori products have many intersecting reaction pathways involving a variety of other substrates such as lipids and enzymes (myeloperoxidase, glutathione peroxidase, glutathione reductase or superoxide dismutase) (Fig. 1). The Amadori rearrangement of D -glucose-primary amine Schiff bases, for example, give 3-deoxyglucosone (3-DG), as shown in Fig. 2. Extensive degradations of the latter give even more reactive (and toxic) vicinal dicarbonyl compounds such as methylglyoxal (MGO) and glyoxal. Many protein-crosslinks can be initiated by methylglyoxal and glyoxal intracellularly, as well as extracellularly. Several such crosslinks involving the e-amino groups of lysine and the guanidino group of arginine have been isolated, and characterized. Among them, pentosidine, a lysine – arginine crosslink, and CML have been extensively studied and implicated in neurodegenerative disorders (Smith et al., 1994b; Castellani et al., 2001). A variety of other crosslinks have been identified in the Maillard reactions. They include methylglyoxal – lysine dimer (MOLD), glyoxal – lysine dimer (GOLD), dilysine crosslinks (crosslines A and B), furosines and b-carbolines (Figs. 1 and 2) (Monnier, 1999; Wang et al., 1999; Pari et al., 2000). Recently, in conjunction with diabetic complications, extensive research has been focused on the trapping of such reactive a-dicarbonyl compounds. Aminoguanidine (NH2NHC( ¼ NH)NH2),

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FIGURE 1 Select pathways of the Maillard reaction and their intersection.

FIGURE 2

Amadori rearrangements and AGEs formation.

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FIGURE 3 AGEs formation from 3-DG.

for example, readily reacts with them to form triazines facilitating their removal (Fig. 4, vide infra). The administration of aminoguanidine in diabetic patients results in the amelioration of diabetic complications, but its clinical use has been abandoned due to adverse effects in some patients in the Phase III clinical trials (Singh et al., 2001).

3-DEOXYGLUCOSONE (3-DG) AND 4-HYDROXYNONENAL (HNE) 3-Deoxyglucosone, derived from the Maillard reaction of glucose with proteins, has been observed both in vitro and in vivo. It inactivates glutathione peroxidase, an enzyme responsible for the detoxification of hydrogen peroxide, leading to increased cellular oxidative stress. It also inactivates glutathione reductase, an antioxidative enzyme. However, major inactivation of the latter enzyme is caused by trans-4-hydroxy-2-nonenal (HNE), a lipid

peroxidation derived product. The involvement of 3-DG in the modification of tissue proteins has been shown by immunocytochemistry using a monoclonal antibody to imidazolone. In a vicious cycle, intracellular oxidative stress causes the enhanced formation of 3-DG, while at the same time 3-DG enhances oxidative stress (Niwa and Tsukushi, 2001). 3-DG also reacts with arginine and lysine residues of proteins in vivo to form pyrraline (Porterootin et al., 1995), pentosidine (Dyer et al., 1991), CML and imidazolones. The latter, CML and imidazolones, are the major AGEs formed in 3-DGmediated protein cross-linking (Fig. 3) (Niwa et al., 1996; 1997c). 3-DG is associated with the onset of AD, as the derived Amadori products, pyrraline (Perry et al., 1999), CML and pentosidine (Takeda et al., 1998; Castellani et al., 2001), have been identified in AD (Shoda et al., 1997; Takeda et al., 1998). In cultured neuronal cells, the formation of CML in the presence of the 3-DG can be prevented by the addition of aminoguanidine (Niwa et al., 1998). The latter reacts

FIGURE 4 Reaction of 3-DG with aminoguanidine.

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FIGURE 5

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Michael reactions of HNE with glutathione, lysine, arginine, and cysteine.

with the carbonyl groups of 3-DG, inhibiting its deleterious effects (Fig. 5). Although 3-DG, by it self, has not been observed in cases of AD, the Amadori precursors of 3-DG, the hexose – lysine adducts, have been detected in the cerebrospinal fluid using a monoclonal antibody to hexitol – lysine. They are 1.7-fold higher in AD patients as compared to normal age-matched controls (Shuvaev et al., 2001). HNE is also clearly involved in the pathogenesis of AD, is neurotoxic and, crucially, modifies t-protein (Sayre et al., 1997; Perez et al., 2000; Takeda et al., 2000). It also modifies the t-protein in progressive supranuclear palsy (PSP), in which the levels of HNE are increased 1.6-fold as compared to control tissues (Odetti et al., 2000). HNE, in addition, decreases glucose and glutamate transport in neurons, and down-regulates cholinergic markers (Pedersen et al., 1999). Glutathione, a tripeptide, blocks the deleterious effects of HNE in non-neuronal cells, by its Michael addition to HNE. Thus the Michael reaction of HNE with the thiol group of the cysteine residue of glutathione effectively inhibits its reactions with lysine, serine and guanidine residues of the proteins (Fig. 5). In other words, glutathione detoxifies HNE in non-neuronal cells, preventing its further deleterious modification of proteins. Mark and coworkers have shown that glutathione attenuates the neurotoxicity of HNE in neuronal cells (Mark et al., 1997). They have suggested that the HNE mediates Amyloid-b induced oxidative damage to neuronal membrane proteins, which, in

turn, leads to disruption of ion homeostasis and cell degeneration. Interestingly, while HNE and glycoxidation products have been found in significant amounts in AD, glycoxidation products are lacking in PSP (Odetti et al., 2000). Neuronal HNE immunoreactivity in PSP is directly proportional to the concentration of NFTs, which implicates the role of HNE in the formation of NFTs in PSP. However, mechanisms other than HNE, such as glycation of tau-protein also contribute to the formation of NFTs in AD (vide infra ).

PROTEIN CROSSLINKS A variety of protein-crosslinks resulting from the Maillard reactions have been identified in vivo and in vitro. Pentosidine, pyrraline and CML have been implicated in neurodegenerative diseases. Other crosslinks such as MOLD, GOLD, crosslines, argpyrimidine and imidazolidinones have not been observed in AD as yet. We summarize the major AGE-related crosslinks below. Pentosidine Glucose, fructose, ribose and ascorbate react with lysine- and arginine-containing proteins to give arginine– lysine crosslink, pentosidine, which was first isolated from brain tissues by (Sell and Monnier, 1989). It is formed by the condensation of the Maillard reaction products of pentoses with arginine

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FIGURE 6 Formation of pentosidine.

and lysine residues of the proteins (Sell et al., 1991). The exact mechanism of formation of pentosidine is unknown and is complicated by the fact that it can be formed not only from pentoses but also from hexoses and ascorbic acid (Fig. 6) (Grandhee and Monnier, 1991). It is commonly used as a marker of carbohydrate metabolism in diabetes, aging and uremia in humans and other animals. Pentosidine has been identified in lipofuscin pigments of AD and aged brains (Horie et al., 1997), and is prominent in the fiber-like structure within the neuropil and the cores of classical senile plaques (Vitek et al., 1994; Smith et al., 1994a; Castellani et al., 2001). The colocalization of the pentosidine with hexitol – lysine adducts further demonstrates the glycoxidative origin of the pentosidine at these sites. The fluorescent properties of the lipofuscin pigments in the AD brain may well result from the glycoxidative products, which include pentosidine. It was immunochemically observed that pentosidine and other AGEs co-localize with astrocytes and microglial cells, whose activation may enhance oxidative stress in AD (Takeda et al., 1998; Castellani et al., 2001). The levels of pentosidine and pyrraline are significantly increased in Down syndrome (DS) fetal brains as compared to controls, which suggests that accelerated brain glycoxidation occurs very early in the life of Down syndrome patients (Odetti

FIGURE 7

et al., 1998b). Down syndrome shows pathological features common to AD and, in both cases, overproduction of amyloid-b peptide and increased cellular oxidation may lead to elevated levels of pentosidine and CML. Pentosidine has been found immunocytochemically in Pick bodies and ballooned neurons of brain tissues in patients with Pick disease, a neurodegenerative disease associated with dementia (Kimura et al., 1996). Although pentosidine is elevated in the serum of diabetic patients (Sell et al., 1998), it is not significantly elevated in AD and Down syndrome, as shown by Seidl and coworkers by using HPLC techniques (Seidl et al., 1997). They assayed the frontal cortex specimens of AD and DS patients for pentosidine and CML by reversed phase high performance liquid chromatographic methods, and showed that their levels are comparable to those of normal controls (vide infra ).

Argpyrimidine The Maillard reaction products from reducing sugars include hydroxyacetone, aminoacetone, as well as methylglyoxal (MGO), an a-dicarbonyl compound. The later reaction product rapidly reacts with arginine-containing proteins to give the protein modification argpyrimidine (Shipanova et al., 1997). Argpyrimidine has been shown to be elevated in the serum of diabetic patients by using HPLC techniques (Sell et al., 1998). The formation of the argpyrimidine is proposed to involve the intermediate formation of the diketone, 3-hydroxypentan-2,4-dione, through a condensation reaction of two molecules of methylglyoxal (Fig. 7). The diketone, once formed, is thought to react with arginine to form the Schiff base, which is expected to aromatize by dehydration (Glomb et al., 2001). The

Proposed aldol-type mechanism for the formation of argpyrimidine.

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FIGURE 8 Mechanism of the formation of Pyrraline from 3-DG and lysine.

proposed mechanisms for the formation of the diketone through aldol type condensations deserve to be scrutinized in further detail, in view of the significance of the argpyrimidine as a marker in aging and possibly in neurodegeneration. Nagaraj and coworkers have synthesized argpyrimidine and characterized it by spectral means (Shipanova et al., 1997). Using this fluorophore as authentic material, they have confirmed its presence in the incubation mixtures of methylglyoxal and proteins in vivo in human lenses. Methylglyoxal, the precursor of argpyrimidine, is formed by the nonenzymatic Maillard reaction of ascorbate, among other pathways. The argpyrimidine concentrations in brunescent cataractous lenses are sevenfold greater than in age matched noncataractous lenses. Pentosidine is present in these lenses in much smaller amounts, roughly 20 to 25-fold lower concentrations. Interestingly, argpyrimidine is stable to acid hydrolysis for extended times, facilitating its quantification by HPLC (Wilker et al., 2001). Pyrraline Pyrraline (e-[2-formyl-5-hydroxymethyl-1H-pyrrolyl]-L -lysine; also named as (S)-e-pyrrolyllysine), the nonenzymatic reaction product of glucose and lysine residues of proteins, is also implicated in AD and other age related diseases such as cataracts. The mechanism of the formation of pyrraline in the Maillard reactions is shown in Fig. 8. The Maillard reaction of glucose with the free amino groups of proteins gives 3-DG as an intermediate, which may react with lysine residues on proteins to give the Schiff base, the acid-catalyzed cyclization and dehydration of which is expected to give pyrraline. The reaction of lysine e-amino group with two mole

equivalents of methylglyoxal, followed by acidcatalyzed rearrangements, may also form pyrraline. Pyrraline has also been detected as a major modification of bovine lens alpha-crystallins when incubated with 3-DG (Nagaraj and Sady, 1996). Mechanistic aspects delineating these two possibilities await further experimentation. Pyrraline, as well as its protein adduct, is significantly increased in diabetic and nondiabetic uremic plasma, as compared to healthy individuals. It has been speculated that circulating pyrraline could contribute to some complications of uremia (Odani et al., 1996). The in vivo presence of pyrraline is demonstrated by immunocytochemical and chromatographic methods (Hayase et al., 1989; Miyata and Monnier, 1992). Smith, Perry and coworkers also identified pyrraline and CML as the major epitopes for the AGE antibodies, immunocytochemically, in NFTs of AD. They have confirmed their detection by the observation of little or no staining in the apparently healthy neurons from the same brains (Smith et al., 1994b). Pyrraline is associated with the lesions of AD and PSP, as shown by immunochemical analyses (Odetti et al., 2000). The latter disease is similar to AD as it also involves the formation of extensive NFTs. Immunoreactivity to pyrraline was seen in the substantia nigra of Parkinson disease and the neocortex of diffuse Lewy body disease and in the Rosenthal fibers in patients with Alexander disease (Castellani et al., 1996; 1997; 2001; Odetti et al., 2000). The Lewy bodies, characteristic for the Lewy body disease and Parkinson disease, are the densely crosslinked intracellular protein deposits formed from neurofilament components and a-synuclein through the intermediacy of a variety of AGEs. AGE promoted formation of Lewy bodies are thought to

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FIGURE 9 Formation of dipyrraline ether and pyrraline cysteine thio-ether.

be very early causative changes rather than late “epiphenomenons” of Parkinson disease (Munch et al., 2000). The glycoxidation and the accompanying formation of pyrraline were shown to occur very early in the life of the Down syndrome patients (Odetti et al., 1998b). AGE inhibitors such as tenilsetam could be used to inhibit formation of the pyrraline (Shoda et al., 1997), by scavenging the intermediate Maillard reaction products (vide infra ). The in vitro reaction of pyrraline with N-aacetylcysteine results in the formation of the thio ether and dipyrraline ether (Fig. 9) (Nagaraj et al., 1996a). These products are formed by the acid catalyzed dehydration at the hydroxymethyl group, followed by nucleophilic attack of the hydroxyl group from the other pyrraline molecule. The reaction of pyrraline with hydroxy-amino acids such as hydroxylysine and hydroxyproline gives minor condensation products (Monnier et al., 1996). However, glutathione undergoes addition reaction with pyrraline to give unstable products, which prompted the discovery of further reactions of pyrraline with proteins, giving rise to additional cross-links (Nagaraj et al., 1996a). Such cross-links

remain to be isolated in in vivo studies. Perhaps due to this ready reaction of pyrraline with the thiol residues of cysteines, to give thio-ethers and its ready dimerization to the dipyrraline ether, the detection of pyrraline in vivo in diseased states is not as straightforward as with other AGEs, such as pentosidine and CML. MOLD and GOLD Glyoxal and methylglyoxal also form crosslinks between two lysine units, known as glyoxal – lysine dimer (GOLD) and methylglyoxal – lysine dimer (MOLD), respectively (Fig. 10). Using HPLC and LCQ/MS/MS these dimeric forms of lysine have been detected in small amounts in cataractous lenses (Nagaraj et al., 1996b; Chellan and Nagaraj, 1999). Micromolar quantities of lysine –lysine cross-links have been isolated from the sugar-mediated crosslinking of a-biotinylated lysine to cysteamine – agarose support (Linetsky et al., 2001). The mechanistic details of this reaction are not well understood. Other related crosslinks of arginine and lysine, named as GODIC and MODIC have recently been isolated from bovine serum albumin (BSA) (Fig. 11)

FIGURE 10 Formation of the MOLD and GOLD.

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FIGURE 11

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Formation of the arginine crosslinks, MODIC and GODIC.

(Lederer et al., 1998; Lederer and Buhler, 1999; Lederer and Klaiber, 1999).

Carboxymethyllysine (CML) and Carboxymethylvaline (CMV) CML (Fig. 12) is one of the acid-stable AGEs, isolated from human cataractous lenses and diabetic tissues. It has been observed in amyloid-b of AD (Uesugi et al., 2000) and in brains from cases of Down syndrome (Odetti et al., 1998a). It is derived from the glycoxidative modifications of the lysine residues of the proteins and has been detected in NFTs using immunocytochemistry techniques. Castellani and coworkers observed co-localized CML with pyrraline, HNE, and pentosidine in the NFTs (vide supra ) (Castellani et al., 2001). CML can form by two distinct routes: (a) lipid peroxidation and (b) advanced glycation, whereas pentosidine is formed exclusively by the latter route. These results provide evidence for the occurrence of two distinct oxidative processes acting in concert in AD neuropathology; i.e. glycoxidations and free-radical mediated oxidative pathway may both contribute to the AD. The cellular distribution of CML in aged and AD brains has been assessed immunohistochemically (Takeda et al., 2001). Electron microscopy revealed that neuronal CML forms granular or linear deposits in neurons and glial deposits. CML, in association with the redox active transition metals, may be responsible for increased carbonyl stress. Increased carbonyl stress may, in turn, may contribute to NFT formation, although little experimental evidence is available to substantiate it. Copper binding to this post-translational modification oxidizes ascorbate in the presence of H2O2 (Saxena et al., 1999). The ascorbate oxidation is suppressed by added chelators such as DTPA indicating the importance of the redox active

transition metals in the glycoxidation reactions mediated by CML. CML and its associated redox transition metals may be potential contributors to glycoxidation of modified tau-proteins, as Ko and coworkers observed extensive glycoxidation of the latter (Ko et al., 1999). The CML-protein complexes, in the presence of metal ions such as Cu2þ may form reactive OH radicals that are responsible for further lipid peroxidation. The formation of CML under physiological conditions (pH 7.4, 378C) was demonstrated by Baynes and coworkers. CML was detected as the major product of N a-formyl-N e-fructose-lysine incubation in phosphate buffers under both aerobic, and anaerobic conditions (Zyzak et al., 1995). However, it was later shown that the oxygen is not required for the browning and crosslinking of proteins by pentoses since pentosidine forms from the incubations of pentoses and RNase A under anaerobic conditions, even though glyoxal and CML were not observed under these conditions. Baynes and coworkers suggested that the antioxidant therapy for diabetic complications may not be very useful based on these conflicting results (Litchfield et al., 1999). In addition, the ultraviolet-induced oxidation may accelerate CML formation as recently demonstrated in the actinic elastosis of photo-aged skin, using a monoclonal antibody to AGE (6D12) whose epitope is CML (Mizutari et al., 1997). CMV (Fig. 12) has recently been isolated from glycated hemoglobin (Hb), and quantified by selected ion monitoring GC/MS. Glycation of hemoglobin occurs largely through lysine and N-terminal valine residues. Glycation of the lysine residues would result in the formation of CML, whereas glycation of the valine residues would give CMV. GC/MS characterization of the esterified hemoglobin CMV indicated that mouse, rat and human have 6, 5 and 14 nmol/g Hb, respectively (Cai and Hurst, 1999).

FIGURE 12 Structures of CML and CMV.

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FIGURE 13 Formation of CML from glyoxal.

The mechanism of the formation of the CML and CMV is not yet clearly established. Sayre and coworkers hypothesized that the CML results from the tautomerization of the glyoxal adduct of lysine (Fig. 13) (Sayre et al., 2001). Alternatively, by a similar mechanism, CML also may form from adduction of glyoxalic acid with lysine by an intermolecular hydride ion transfer from the hydrate of methylglyoxal (or other carbonyl-hydrates), an abundant intracellular constituent, derived from the Maillard reaction or lipid peroxidation, as shown below (Fig. 14). It is most likely that the latter pathway predominates in vivo, in view of the abundant intracellular concentrations of methylglyoxal. Similar mechanisms may account for the formation of CMV. Crosslines Crosslines are the AGEs formed from the reaction of e-amino groups of lysine with D -glucose. Two diastereomeric crosslines, named crossline-A and crossline-B (Fig. 15) have been synthesized by the reaction of N a-acetyl-L -lysine and glucose and characterized thoroughly (Nakamura et al., 1992). The mechanism of their formation is not clearly established, and may involve the condensation of two hexose units derived from the 3-DG with two lysine units. The in vivo occurrence of the crosslines in rat lens proteins has been established by immunochemistry with the use of polyclonal antiserum specific to the

crossline hapten (Obayashi et al., 1996). Elevated amounts of crosslines were found in cataractous lenses when compared to age-matched controls. The in vitro experiments indicate that crosslines form in a time-dependent manner and have a fluorescence spectrum of 379 (Ex)/463 (Em), which is comparable with those of other AGE products (cf., Pentosidine 335 (Ex)/385 (Em)). Crosslines also have been implicated in diabetic retinopathy where it has been shown by enzyme linked immunosorbent assay (ELISA) that patients with Type 2 diabetes mellitus have significantly higher erythrocyte membrane protein (EMP)-crossline concentration in their blood samples (Yamaguchi et al., 1998). The EMP crossline levels were elevated 1.6-fold in diabetic patients without retinopathy ð7:6 ^ 0:5 pmol=mgÞ; 2.2-fold in diabetic patients with non-proliferative retinopathy (10.5 pmol/mg) and 2.6-fold in diabetic patients with proliferative retinopathy ð12:0 ^ 0:6 pmol=mgÞ as compared to healthy control subjects ð4:7 ^ 0:5 pmol=mgÞ: The crosslines, like other AGEs may prove to be useful markers of agerelated diseases. Their occurrence in neurodegeneration is worth investigating. Imidazolidinone Crosslinks Imidazolidinone crosslinks are the AGEs derived from the reaction of the guanidine groups of the arginine residues of the proteins with the adicarbonyl compounds. They are detected immunocytochemically in kidneys and aortas of diabetic

FIGURE 14 Formation of CML from glyoxylic acid.

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FIGURE 15 Structures of Crosslines A and B.

patients (Niwa et al., 1997a). They have been isolated from the incubation mixture of 3-DG and arginine derivatives (e.g. N-a-benzoylarginine amide) under physiological conditions (at 378C and pH 7.4) (Hayase et al., 1995). The localization of the imidazolone in the amyloid tissues of diabetic rats was detected by immunochemistry using a monoclonal antibody to imidazolone (Niwa et al., 1997b). Under certain circumstances, it is possible for glycated protein to undergo non-Amadori type rearrangements to give modified proteins. Horvat and coworkers have shown one such modification that involves the formation of the imidazolidin4-ones from the reaction of esters of leucine – enkephalin (H-Tyr-Gly-Phe-Leu-OH) derived from the C6-OH group of D -glucose, D -galactose, or D -mannose (Fig. 16). The reaction involves the formation of a cyclic ester in which the carbonyl group of the D -glucose forms an amidine linkage at the tyrosine end. Hydrolysis using aqueous alkali gives the imidazolidinone with a free carboxy terminus (Horvat et al., 1998; 1999). The glucose-derived imidazolidinones also have been characterized using mass spectrometric techniques such as FAB-MS/MS and ESI-MS/MS (Roscic

et al., 2001). Such rearrangements have not been observed in vivo.

ANALYTICAL METHODS Many of AGE products are isolated and characterized by conventional spectroscopic methods. Analysis of the product mixture in the Maillard reactions is a formidable task since there are a multitude of products formed ranging from small molecules to large polymers. A variety of HPLC and GC/MS methods are routinely used for analyzing the volatile components of the reaction (Porretta, 1992; Coleman, 1999; Monti et al., 1999; Lapolla et al., 2001). High resolution and multinuclear NMR can be used for monitoring the progress of the Maillard reaction (Tessier et al., 1999; Madaj et al., 2000). Tandem mass spectrometry (MS/MS) can be used to characterize the structures of the products when they are formed in insignificant amounts. In such cases, comparison with authentically synthesized samples is useful for the confirmation of the structures. Capillary electrophoresis coupled to electrospray ionization mass spectrometry (CE/ESI-MS) has recently been used as

FIGURE 16 Formation of an imidazolidinone crosslink from the Leucine– enkephalir.

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FIGURE 17 The Maillard reaction of 5-hydroxymethylfurfural.

an improved analytical technique for characterizing molecules of extremely high hydrophilicity (Tomlinson et al., 1993). However, this process may give erroneous results due to the unwanted analyte clustering produced during the electrospray ionization, especially when high concentrations of the analytes are used. By using 15N isotopes, it was possible to overcome the ion-clustering problem inherent in the ESI method. This technique is demonstrated using a model reaction involving 5-hydroxymethylfurfural and lysine (14N and 15N labeled) to give 2-formyl-5-(hydroxymethyl)-N-carboxymethylpyrrole, as one of the early products (Fig. 17). CE-MS analysis of a 1:1 (v/v) mixture of 14N and 15 N labeled product mixtures readily distinguishes the expected molecular ion peaks from the ion clusters. The tandem mass spectrometry of the isotopically pure analytes further simplifies the problem (Benson et al., 1998). Capillary electrophoresis is useful for the analysis of Maillard products from the reaction of glyceraldehydes and the N a-acetyllysine. The major components are separated and detected by UV spectroscopy, at 214 nm (De Sa et al., 2001). Electrophoretic techniques, such as two-dimensional gel electrophoresis and capillary electrophoresis, are used to monitor the progress of the Maillard reactions (Fayle et al., 2001). Capillary electrophoresis is complimentary to the reverse-phase HPLC for the separation of Maillard reaction products of glucose or xylose and glycine (Royle et al., 1998). HPLC coupled with a diode array detector can be used for the quantification of the various Maillard products derived from the reaction of ascorbate with lysine (Larisch et al., 1998). The a-dicarbonyl compounds formed in the Maillard reactions can be removed by reacting with o-phenylenediamine (OPD) to give the quinoxaline derivatives, which can be identified and quantitized through HPLC, GC, or GC/MS techniques (Homoki-

Farkas et al., 1997). Post-column derivatization could also be achieved by using additional columns containing the OPD attached to the main column (Eichner et al., 1990; Nagaraj et al., 1996b). Immunological identification of the AGEs has recently attracted much attention in view of the extremely low levels of these products formed in vivo and limits in detection levels by these methods. NonCML AGE antibodies have been prepared and reacted with the proteins modified by glyceraldehyde or glycolaldehyde. The studies identified several AGEs formed in vivo by reaction of proteins with short-chain a-dicarbonyl compounds. Immunocytochemical studies were performed to elucidate the role of AGEs in amyloidosis associated with AD. While early studies suggested that the AGEs may not be involved in the amyloidosis of AD (Kimura et al., 1995), subsequent immunocytochemical studies showed that CML and pentosidine are involved with the lesions of AD and also pick disease (Castellani et al., 2001).

GLYCATION OF AMYLOID-b AND t-PROTEIN The glycation of amyloid-b peptide, the constituent of the senile plaques in AD may contribute to its cross-linking. There are strong indications that the glycation of amyloid-b peptide and t-protein occurs in the early stages of AD, although it has been hypothesized that peptide free radicals generated by amyloid-b would cross-link peptides with sugars resulting in glycation (Mattson et al., 1995). The protein PHF-t/A68, a precursor for NFTs, has been shown to be modified by AGEs and HNE (Takeda et al., 2000), strongly implicating early glycation and lipid peroxidation in AD (Ledesma et al., 1994; Yan et al., 1994). Glycated amyloid-b and t-proteins may induce the formation of free radicals and enhance the

FIGURE 18 Structure of some AGE inhibitors.

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aggregation of tau and amyloid-b into NFTs and senile plaques, respectively. Recently, tenilsetam, the racemic 3-(2-thienyhl)2-piperazinone (Fig. 18), has been tested as an AGE inhibitor in the Maillard reactions in vitro and in vivo (Dukic-Stefanovic et al., 2001). Shoda and coworkers have tested tenilsetam as the AGE inhibitor in the streptozotocin-induced diabetic rats and found that the levels of AGE-derived fluorescence and pyrraline were dramatically decreased, as compared to the control subjects (Shoda et al., 1997). Other experimental drugs such as carnosine and penicillamine (Fig. 18) markedly improve cognition and memory in AD patients, presumably by reducing the crosslinks associated with amyloid-b or tau (Munch et al., 1994; 1997a). Wang and coworkers found that the glycation led to abnormally hyperphosphoryated t-protein in PHFs of NFTs (Wang et al., 1996a); whereas the tau from the paired helical filaments (PHF) could be stained by lectins, however normal tau was inert to lectins. Further, upon in vitro deglycosylation, PHF untwisted into thick straight filaments, based on which it has been hypothesized that tau from only AD patients is glycated. Deglycosylation and dephosphorylation of PHF, in addition, restored the microtubule polymerization activity of tau (Wang et al., 1995; 1996b). PHF-tau has been shown to be non-enzymatically glycated (Ledesma et al., 1994) and ubiquitinated (Morishima-Kawashima et al., 1993). Tau glycation has also been shown immunocytochemically, giving strong support for the hypothesis that glycation plays a role in the formation of PHF (Takahashi et al., 1999). High mannose-type sugar chains and truncated N-glycans were the major components of PHF (Sato et al., 2001). Amyloid-b protein precursor (AbPP) has been shown to be N- and O-glycosylated, a process that may promote neurite outgrowth and branching (Salinero et al., 2000). Using immunocytochemistry, it was shown that AGEs accumulate in the aging human brain in the pyramidal neurons, which are vulnerable and degenerate in AD (Li et al., 1995). The Maillard-reaction-mediated modification of t-protein and amyloid-b protein may lead to lesion formation in AD by promoting cross-links, insolubility and decreased resistance to protease enzymes. Studies using antibodies specific to pyrraline and pentosidine ligands, also indicate the presence of these modifications in senile plaques and NFTs of AD (Smith et al., 1995b). Methylglyoxal, the glycoxidative or lipoperoxidative product, is also involved in the formation of intracellular cross-linked proteins, making them insoluble. These protein aggregates can prevent cellular transport and result in neuronal dysfunction and cell death. CML also was shown to be a constituent of PHF in AD brains. Thus using specific

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antibodies to CML, immunoblot analysis showed CML immunoreactivity in PHF-tau (both soluble and insoluble fractions). Immunoelectron microscopic analyses indicated that the anti-CML antibody labels predominantly PHF in aggregates (Ko et al., 1999). Cerebrospinal fluid (CSF) contains elevated amounts of butyrylcholinesterase (BuChE) and acetylcholinesterase (AchE) compared to normal brains. These proteins are glycated, the extent of glycation serving as a marker for the progression of AD, as in the case of amyloid-b and tau-protein (Saez-Valero and Small, 2001). Further, Shuvaev and coworkers have shown that many major proteins of CSF were glycated (Amadori product) in aging and AD. These include albumin, apolipoprotein E and transthyretin. However, these modifications were not specific as all of the proteins examined are also modified. The glycoxidations of the lipoproteins associated with amyloid-b in the CSF (Schippling et al., 2000) may indeed be an initiator of neurodegeneration. The co-localization of the redox active transition metals with the modified proteins clearly shows the importance of oxidative stress in the onset of these diseases. The protein deposits are also immunoreactive to antibodies recognizing protein sidechains modified by reactive oxygen species (ROS), reactive nitrogen species (RNS), or glycoxidation (Sayre et al., 2001). It has been shown that transitionmetal-mediated glycoxidation accelerates the crosslinking of amyloid-b (Loske et al., 2000). Thus, in vitro experiments involving the incubation of glucose and synthetic amyloid-b show the appearance of the covalently cross-linked high molecular weight amyloid b oligomers, whose concentration increases with increasing amounts of Cu þ/Cu 2þ and Fe2þ/Fe3þ ions. Metal chelators and antioxidants effectively suppress the formation of such amyloid b aggregation. Glycoxidation of proteins generates free carbonyl groups in the proteins, which are normally detected by 2,4-DNP reactions. Smith and coworkers developed an immunocytochemical technique for the detection of the free carbonyl groups using 2,4-dinitrophenylhydrazine labeling linked to an antibody system. Using this technique they were able to demonstrate lipoperoxidative and glycoxidative modifications of the proteins of brain tissues in AD (Smith et al., 1998). Seidl and coworkers, on the other hand, measured the concentrations of pentosidine and CML from the frontal cortex using HPLC, and found similar concentrations in both AD and agematched controls. They concluded that glycation and glycoxidation is not an important factor in AD (vide supra ) (Seidl et al., 1997), although it is also likely that there may be localized high concentrations of glycoxidation in certain regions of the brain that

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are lost during the extraction of tissue for HPLC analysis. Glycoxidation-mediated AGE formation may play a role in inciting local inflammatory reactions in AD lesions (Dickson, 1996), which may, in turn, increase cytokine-stress through receptor-mediated interactions between glia and the amyloid-b ligand (Li et al., 1998). Hyaluronic acid with a molecular weight above 1.2 MDa inhibits the AGE-induced activation of the transcription factor NF-kb and the NF-kbregulated cytokines interleukin-1-a, interleukin-6 and tumor necrosis factor-a (Neumann et al., 1999). However, its protective action diminishes with aging as it breaks down into lower molecular weight components due to the enhanced oxidative stress.

MAILLARD REACTION PRODUCTS AS ANTIOXIDANTS Maillard reaction products exhibit antioxidant properties in vitro, perhaps by inhibiting the formation of superoxide anion and hydroxyl (OH) radical species, or by destroying them. Glucose – glycine mixtures have been shown to inhibit OH radical species by over 90% (Yoshimura et al., 1997) using ESR techniques. The mechanism of inhibition may involve not only the direct scavenging of the OH radical but also chelation of the Fe2þ species, which is responsible for the production of the OH radicals by the Fenton reaction. The Maillard reaction also produces ROS such as OH radicals and superoxide radical anions, and at the same time, the higher molecular weight products derived from the reaction are scavengers of ROS (Okamoto et al., 1992). Free radical formation in Maillard reactions, involving secondary amines and glyceraldehydes, has been demonstrated using ESR spectroscopy (Roberts and Lloyd, 1997). These findings make it clear that whether AGEs are pro- or antioxidant depends upon cellular circumstances.

RECEPTORS FOR ADVANCED GLYCATION END PRODUCTS (RAGE) The RAGE have been implicated to play a major role in the onset of the AD. RAGE is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules in which AGEs and amyloid fibrils act as ligands (Schmidt et al., 2000). RAGE receptor expression is upregulated at sites of pathologies associated with AGEs (Schmidt et al., 1999). It is expressed in normal as well as amyloid-rich tissues such as microglia in AD (Yan et al., 1997). Polyclonal antibodies developed for RAGE proteins recognize full length RAGE (50 kD) and N-terminal RAGE (35 kD) in human brain tissue.

AGE and RAGE are expressed in the astrocytes of AD patients but not those of diabetes mellitus (DM) patients, which implies that glycated amyloid-b is taken up via RAGE and degraded through the lysosomal pathway in astrocytes. RAGE has also been shown to be the neuron cell receptor for amyloid-b (Li et al., 1998; Yan et al., 2000). The receptor-mediated reactions may further contribute to neuronal degeneration (Sasaki et al., 2001). Amyloid-b-(1-40)-mediated migration of monocytes was inhibited by the antibody to the corresponding RAGE. The latter suggests that the increased diapedesis of monocytes across blood – brain barrier, in response to amyloid-b, may play a role in the pathogenesis of amyloid-b-related vascular disease (Giri et al., 2000). Yan and coworkers have shown that the RAGE is a receptor for the amyloid b peptide (Yan et al., 1996). Glycated residues are also ligands for other scavenger receptors (e.g. CD 36) (Ohgami et al., 2000; 2001). The RAGEs, in addition to their wide distribution in cortical neurons, are also expressed in microglia and astrocytes of both normal and AD patients. Amyloid-b-RAGE interaction activates NFkB, resulting in neuronal upregulation of macrophage-colony stimulating factor (MCSF) (Yan et al., 1998).

AGE INHIBITORS The formation of the AGEs can be potentially inhibited by using specific inhibitors, which rapidly react with the a-dicarbonyl compounds, derived from the Amadori products. Some of these inhibitors prevent AGE-mediated cross-linking (Forbes et al., 2001). Aminoguanidine and its modifications were shown to be effective for trapping as they react rapidly with a-dicarbonyl compounds. Although guanidine also can react with such a-dicarbonyl compounds, it is not as reactive as aminoguanidine, preventing its widespread usage. Perhaps, derivatives of arginine also may play a role in trapping carbonyl compounds. Aminoguanidine is especially suitable for trapping a-dicarbonyl compounds such as methylglyoxal, which is highly prone to protein cross-linking as well as generating ROS in the course of glycoxidation reactions. Aminoguanidine may prove to be beneficial in treating AD, as in diabetes. Unfortunately, the clinical phases in the aminoguanidine treatment were ended due to complications in diabetic patients. Other compounds having similar activity are D -penicillamine (perhaps due to metal binding) (Mcpherson et al., 1988), thiamine pyrophosphate and pyridoxamine (Booth et al., 1997), arylureido phenoxy isobutyric acid and related molecules (Rahbar et al., 1999). Most of these compounds are

MAILLARD REACTIONS AND ALZHEIMER DISEASE

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FIGURE 19 AGE inhibitors.

inhibitors of the post-Amadori glycation, and show their effectiveness by trapping the reactive adicarbonyl intermediates. Anti-inflammatory compounds such as indomethacin and acetylsalicylic acid are also examined as inhibitors of the Maillard reaction (Colaco et al., 1996). They may act as inhibitors by preventing the oxidative stress associated with the formation of the AGE. Cerami and coworkers have reported a new class of AGE inhibitors, which reverse crosslinking. Compounds such as N-phenacylthiazolium bromide (PTB) and 4,5-dimethyl-3-phenacylthiazolium chloride (DPTC) (Fig. 19) were shown to be effective in such attempts (Wolffenbuttel et al., 1998a,b). They react with and cleave the covalent, AGE-derived protein crosslinks. As there are a variety of crosslinks, a variety of mechanism-based breakers of AGEs need to be explored. Tenilsetam, was shown to have beneficial therapeutic effects in AD, by acting as an AGE-binding compound (Fig. 18, vide supra) (Colaco and Harrington, 1996). It inhibits protein crosslinking by AGEs, by its attachment to the glycated proteins (Munch et al., 1994). It also inhibits glucose- and fructose-induced polymerization of lysozyme in a concentration dependent manner in vitro, and significantly decreases the AGEs such as pyrraline and CML in vivo (Shoda et al., 1997). Due to the heterogeneity of the etiological factors and difficulty in the diagnosis of the early stages of the AD, therapeutic approaches to AD have not met with proven success. In addition to the AGE-inhibitors, several antioxidants are being currently studied in this direction. Some clinical data point to the anti-dementive properties for gingko biloba, selegiline and vitamins C and E (Rosler et al., 1998). The antioxidants such as vitamin A are effective radical scavengers, and may also prevent the glycoxidation, leading to the reduced formation of the AGEs. Pyridoxamine and thiamin pyrophosphate have been shown to be effective inhibitors of AGEs from the post-amadori products. Pharmacological approaches are being developed to enhance cholinergic function; the acetylcholinesterase inhibitors (physostigmine and tacrine), donepezil hydrochloride (Sugimoto, 1999), and anti-inflammatory drugs and hormones such as indomethacin and estrogens show some effect on

cognition and the behavioral symptoms associated with AD (Heidrich et al., 1997; Frey et al., 2000). Clearly, understanding the mechanistic aspects of the AD, especially the glycoxidation that leads to AGE formation has an important bearing on the development of novel therapeutics.

Acknowledgements One of the authors (V.P.R.) thanks Professor Ekkehard Sinn for helpful comments and encouragement.

References Baynes, J.W. and Thorpe, S.R. (1999) “Role of oxidative stress in diabetic complications—a new perspective on an old paradigm”, Diabetes 48, 1–9. Bence, N.F., Sampat, R.M. and Kopito, R.R. (2001) “Impairment of the ubiquitin– proteasome system by protein aggregation”, Science (Washington, DC, US) 292, 1552–1555. Benson, L.M., Naylor, S. and Tomlinson, A.J. (1998) “Investigation of Maillard reaction products using 15N isotope studies and analysis by electrospray ionization-mass spectrometry”, Food Chem. 62, 179– 183. Booth, A.A., Khalifah, R.G., Todd, P. and Hudgon, B.G. (1997) “In vitro kinetic studies of formation of antigenic advanced glycation end products (AGEs). Novel inhibition of postAmadori glycation pathways”, J. Biol. Chem. 272, 5430–5437. Brownlee, M. (1995) “Advanced protein glycosylation in diabetes and aging”, Annu. Rev. Med. 46, 223–234. Cai, J. and Hurst, H.E. (1999) “Identification and quantitation of N-(carboxymethyl)valine adduct in hemoglobin by gas chromatography mass spectrometry”, J. Mass Spectrom. 34, 537 –543. Castellani, R., Smith, M.A., Richey, P.L. and Perry, G. (1996) “Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease”, Brain Res. 737, 195–200. Castellani, R.J., Perry, G., Harris, P.L.R., Monnier, V.M., Cohen, M.L. and Smith, M.A. (1997) “Advanced glycation modification of Rosenthal fibers in patients with Alexander disease”, Neurosci. Lett. 231, 79–82. Castellani, R.J., Harris, P.L., Sayre, L.M., Fujii, J., Taniguchi, N., Vitek, M.P., Founds, H., Atwood, C.S., Perry, G. and Smith, M.A. (2001) “Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)–(Carboxymethyl) lysine and hexitol–lysine”, Free Radic. Biol. Med. 31, 175 –180. Chellan, P. and Nagaraj, R.H. (1999) “Protein crosslinking by the Maillard reaction: dicarbonyl-derived imidazolium crosslinks in aging and diabetes”, Arch. Biochem. Biophys. 368, 98 –104. Colaco, C. and Harrington, C.R. (1996) “Inhibitors of the Maillard reaction—potential in the treatment of Alzheimer’s disease”, CNS Drugs 6, 167 –177. Colaco, C., Ledesma, M.D., Harrington, C.R. and Avila, J. (1996) “The role of the Maillard reaction in other pathologies: Alzheimer’s disease”, Nephrol. Dial. Transplant. 11, 7–12.

206

V. PRAKASH REDDY et al.

Coleman, III, W.M. (1999) “SPME-GC-MS detection analysis of Maillard reaction products”, Appl. Solid Phase Microextr., 585 –608. De Sa, P.F.G., Treubig, J.M., Brown, P.R. and Dain, J.A. (2001) “The use of capillary electrophoresis to monitor Maillard reaction products (MRP) by glyceraldehyde and the epsilon amino group of lysine”, Food Chem. 72, 379 –384. Devchand, K. and De Muelenaere, H.J.H. (1996) “Antioxidant activity of Maillard reaction products formed during extrusion”, SA J. Food Sci. Nutr. 8, 144– 148. Dickson, D.W. (1996) “Glycoxidation in Alzheimer’s disease: a specific mechanism of early lesion pathogenesis?”, Alzheimer’s Dis. Rev. (Electronic Publication) 1, 75– 76. Dukic-Stefanovic, S., Schinzel, R., Riederer, P. and Munch, G. (2001) “AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs?”, Biogerontology 2, 19–34. Durany, N., Munch, G., Michel, T. and Riederer, P. (1999) “Investigations on oxidative stress and therapeutical implications in dementia”, Eur. Arch. Psych. Clin. Neurosci. 249, 68– 73. Dyer, D.G., Blackledge, J.A., Thorpe, S.R. and Baynes, J.W. (1991) “Formation of pentosidine during nonenzymatic browning of proteins by glucose. Identification of glucose and other carbohydrates as possible precursors of pentosidine in vivo”, J. Biol. Chem. 266, 11654–11660. Eichner, K., Reutter, M. and Wittmann, R. (1990) “Detection of Maillard reaction intermediates by high-pressure liquid chromatography (HPLC) and gas chromatography”, Maillard React. Food Process., Hum. Nutr. Physiol., (Proc. Intl Symp. Maillard React.) 4, 63 –77. Fayle, S.E., Healy, J.P., Brown, P.A., Reid, E.A., Gerrard, J.A. and Ames, J.M. (2001) “Novel approaches to the analysis of the Maillard reaction of proteins”, Electrophoresis 22, 1518–1525. Forbes, J.M., Soulis, T., Thallas, V., Panagiotopoulos, S., Long, D.M., Vasan, S., Wagle, D., Jerums, G. and Cooper, M.E. (2001) “Renoprotective effects of a novel inhibitor of advanced glycation”, Diabetologia 44, 108–114. Frey, U., Retz, W., Riederer, P. and Rosler, M. (2000) “New aspects in antidemential drug therapy of Alzheimer’s disease”, Aktuelle Neurol. 27, 305 –317. Giri, R., Shen, Y.M., Stins, M., Yan, S.D., Schmidt, A.M., Stern, D., Kim, K.S., Zlokovic, B. and Kalra, V.K. (2000) “beta-Amyloidinduced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1”, Am. J. Physiol.—Cell Physiol. 279, C1772–C1781. Glomb, M.A., Rosch, D. and Nagaraj, R.H. (2001) “N-delta(5-hydroxy-4,6-dimethylpyrimidine-2-yl)-L -ornithine, a novel methylglyoxal– arginine modification in beer”, J. Agric. Food Chem. 49, 366–372. Grandhee, S.K. and Monnier, V.M. (1991) “Mechanism of formation of the Maillard protein cross-link pentosidine. Glucose, fructose, and ascorbate as pentosidine precursors”, J. Biol. Chem. 266, 11649–11653. Hayase, F., Nagaraj, R.H., Miyata, S., Njoroge, F.G. and Monnier, V.M. (1989) “Aging of proteins: immunological detection of a glucose-derived pyrrole formed during the Maillard reaction in vivo”, J. Biol. Chem. 264, 3758–3764. Hayase, F., Konishi, Y. and Kato, H. (1995) “Identification of the Modified structure of Arginine residues in proteins with 3-Deoxyglucosone, a Maillard reaction intermediate”, Biosci. Biotechnol. Biochem. 59, 1407–1411. Heidrich, A., Rosler, M. and Riederer, P. (1997) “Pharmacotherapy in Alzheimer’s dementia: treatment of cognitive symptoms— results of new studies”, Forschritte Neurol. Psychiatr. 65, 108 –121. Homoki-Farkas, P., Orsi, F. and Kroh, L.W. (1997) “Methylglyoxal determination from different carbohydrates during heat processing”, Food Chem. 59, 157–163. Horie, K., Miyata, T., Yasuda, T., Takeda, A., Yasuda, Y., Maeda, K., Sobue, G. and Kurokawa, K. (1997) “Immunohistochemical localization of advanced glycation end products, pentosidine, and carboxymethyllysine in lipofuscin pigments of Alzheimer’s disease and aged neurons”, Biochem. Biophys. Res. Commun. 236, 327–332. Horvat, S., Varga-Defterdarovic, L. and Horvat, J. (1998) “Synthesis of novel imidazolidinones from hexose–peptide adducts: model studies of the Maillard reaction with possible

significance in protein glycation”, Chem. Commun. (Cambridge), 1663–1664. Horvat, S., Roscic, M. and Horvat, J. (1999) “Synthesis of hexoserelated imidazolidinones: novel glycation products in the Maillard reaction”, Glycoconj. J. 16, 391–398. Kimura, T., Takamatsu, J., Araki, N., Goto, M., Kondo, A., Miyakawa, T. and Horiuchi, S. (1995) “Are advanced glycation end-products associated with amyloidosis in Alzheimer’s disease?”, NeuroReport 6, 866 –868. Kimura, T., Ikeda, K., Takamatsu, J., Miyata, T., Sobue, G., Miyakawa, T. and Horiuchi, S. (1996) “Identification of advanced glycation end products of the Maillard reaction in Pick’s disease”, Neurosci. Lett. 219, 95–98. Ko, L.W., Ko, E.C., Nacharaju, P., Liu, W.K., Chang, E., Kenessey, A. and Yen, S.H. (1999) “An immunochemical study on tau glycation in paired helical filaments”, Brain Res. 830, 301 –313. Lapolla, A., Fedele, D., Martano, L., Arico, N.C., Garbeglio, M., Traldi, P., Seraglia, R. and Favretto, D. (2001) “Advanced glycation end products: a highly complex set of biologically relevant compounds detected by mass spectrometry”, J. Mass Spectrom. 36, 370– 378. Larisch, B., Gross, U. and Pischetsrieder, M. (1998) “On the reaction of L -ascorbic acid with propylamine under various conditions. Quantification of the main products by HPLC/DAD”, Z. Lebensm.– Unters. Forsch. A 206, 333 –337. Lederer, M.O. and Buhler, H.P. (1999) “Cross-linking of proteins by Maillard processes-characterization and detection of a lysinearginine cross-link derived from D -glucose”, Bioorg. Med. Chem. 7, 1081– 1088. Lederer, M.O., Gerum, F. and Severin, T. (1998) “Cross-linking of proteins by Maillard processes—model reactions of D -glucose or methylglyoxal with butylamine and guanidine derivatives”, Bioorg. Med. Chem. 6, 993–1002. Lederer, M.O. and Klaiber, R.G. (1999) “Cross-linking of proteins by Maillard processes: characterization and detection of lysine– arginine cross-links derived from glyoxal and methylglyoxal”, Bioorg. Med. Chem. 7, 2499–2507. Ledesma, M.D., Bonay, P., Colaco, C. and Avila, J. (1994) “Analysis of microtubule-associated protein tau glycation in paired helical filaments”, J. Biol. Chem. 269, 21614–21619. Ledl, F. and Schleicher, E. (1990) “New aspects of the Maillard reaction in foods and in the human body”, Angew Chem. Int. Ed. Engl. 29, 565–706. Li, J.J., Surini, M., Catsicas, S., Kawashima, E. and Bouras, C. (1995) “Age-Dependent accumulation of advanced glycosylation end-products in human neurons”, Neurobiol. Aging 16, 69–76. Li, J.J., Dickson, D., Hof, P.R. and Vlassara, H. (1998) “Receptors for advanced glycosylation endproducts in human brain: role in brain homeostasis”, Mol. Med. 4, 46– 60. Linetsky, M., Legrand, R.D., Mossine, V.V. and Ortwerth, B.J. (2001), Appl. Biochem. Biotechnol. 94, 71–96, Sugar-mediated crosslinking of alpha-biotinylated-Lys to cysteamine– agarose support: a method to isolate Maillard Lys–Lys-like crosslinks. Litchfield, J.E., Thorpe, S.R. and Baynes, J.W. (1999) “Oxygen is not required for the browning and crosslinking of protein by pentoses: relevance to Maillard reactions in vivo”, Int. J. Biochem. Cell Biol. 31, 1297–1305. Loske, C., Gerdemann, A., Schepl, W., Wycislo, M., Schinzel, R., Palm, D., Riederer, P. and Munch, G. (2000) “Transition metalmediated glycoxidation accelerates cross-linking of betaamyloid peptide”, Eur. J. Biochem. 267, 4171–4178. Madaj, J., Nishikawa, Y., Reddy, V.P., Rinaldi, P., Kurata, T. and Monnier, V.M. (2000) “6-Deoxy-6-fluoro-L -ascorbic acid: crystal structure and oxidative degradation”, Carbohydr. Res. 329, 477–485. Mark, R.J., Lovell, M.A., Markesbery, W.R., Uchida, K. and Mattson, M.P. (1997) “A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid betapeptide”, J. Neurochem. 68, 255 –264. Mastrocola, D. and Munari, M. (2000) “Progress of the Maillard reaction and antioxidant action of Maillard reaction products in preheated model systems during storage”, J. Agric. Food Chem. 48, 3555–3559. Mattson, M.P., Carney, J.W. and Butterfield, D.A. (1995) “A tombstone in Alzheimer’s?”, Nature 373, 481.

MAILLARD REACTIONS AND ALZHEIMER DISEASE Mcpherson, J.D., Shilton, B.H. and Walton, D.J. (1988) “Role of fructose in glycation and cross-linking of proteins”, Biochemistry 27, 1901– 1907. Miyata, S. and Monnier, V. (1992) “Immunohistochemical detection of advanced glycosylation end products in diabetic tissues using monoclonal antibody to pyrraline”, J. Clin. Investig. 89, 1102– 1112. Mizutari, K., Ono, T., Ikeda, K., Kayashima, K. and Horiuchi, S. (1997) “Photo-enhanced modification of human skin elastin in actinic elastosis by N-epsilon-(carboxymethyl)lysine, one of the glycoxidation products of the Maillard reaction”, J. Investig. Dermatol. 108, 797 –802. Monnier, V.M. (1999) “Glycation, glycoxidation, and other Maillard reaction products”, Methods Aging Res., 657–681. Monnier, V.M., Nagaraj, R.H., Portero-Otin, M., Glomb, M., Elgawish, A., H, ., Sell, D.R. and Friedlander, M.A. (1996) “Structure of advanced Maillard reaction products and their pathological role”, Nephrol., Dial., Transplant. 11, 20–26. Monti, S.M., Ritieni, A., Graziani, G., Randazzo, G., Mannina, L., Segre, A., L, . and Fogliano, V. (1999) “LC/MS analysis and antioxidative efficiency of Maillard reaction products from a lactose – lysine model system”, J. Agric. Food Chem. 47, 1506–1513. Morishima-Kawashima, M., Hasegawa, M., Takio, K., Suzuki, M., Titani, K. and Ihara, Y. (1993) “Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments”, Neuron 10, 1151 –1160. Munch, G., Taneli, Y., Schraven, E., Schindler, U., Schinzel, R., Palm, D. and Riederer, P. (1994) “The Cognition-enhancing drug tenilsetam is an inhibitor of protein cross-linking by advanced glycosylation”, J. Neural Transm.—Park. Dis. Dement. Sect. 8, 193 –208. Munch, G., Mayer, S., Michaelis, J., Hipkiss, A.R., Riederer, P., Muller, R., Neumann, A., Schinzel, R. and Cunningham, A.M. (1997a) “Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide”, Biochim. Biophys. Acta 1360, 17– 29. Munch, G., Thome, J., Foley, P., Schinzel, R. and Riederer, P. (1997b) “Advanced glycation endproducts in ageing and Alzheimer’s disease”, Brain Res. Rev. 23, 134 –143. Munch, G., Cunningham, A.M., Riederer, P. and Braak, E. (1998a) “Advanced glycation endproducts are associated with Hirano bodies in Alzheimer’s disease”, Brain Res. 796, 307–310. Munch, G., Schinzel, R., Loske, C., Wong, A., Durany, N., Li, J.J., Vlassara, H., Smith, M.A., Perry, G. and Riederer, P. (1998b) “Alzheimer’s disease—synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts”, J. Neural Transm. 105, 439 –461. Munch, G., Schicktanz, D., Behme, A., Gerlach, M., Riederer, P., Palm, D. and Schinzel, R. (1999) “Amino acid specificity of glycation and protein-AGE crosslinking reactivities determined with a dipeptide SPOT library”, Nat. Biotechnol. 17, 1006–1010. Munch, G., Luth, H.J., Wong, A., Arendt, T., Hirsch, E., Ravid, R. and Riederer, P. (2000) “Crosslinking of alpha-synuclein by advanced glycation endproducts—an early pathophysiological step in Lewy body formation?”, J. Chem. Neuroanat. 20, 253– 257. Nagaraj, R.H. and Sady, C. (1996) “The presence of a glucosederived Maillard reaction product in the human lens”, FEBS Lett. 382, 234–238. Nagaraj, R.H., Porterootin, M. and Monnier, V.M. (1996a) “Pyrraline ether crosslinks as a basis for protein crosslinking by the advanced Maillard reaction in aging and diabetes”, Arch. Biochem. Biophys. 325, 152–158. Nagaraj, R.H., Shipanova, I.N. and Faust, F.M. (1996b) “Protein cross-linking by the Maillard reaction—isolation, characterization, and in vivo detection of a lysine– lysine cross-link derived from methylglyoxal”, J. Biol. Chem. 271, 19338–19345. Nakamura, K., Hasegawa, T., Fukunaga, Y. and Ienaga, K. (1992) “Crosslines A and B as candidates for the fluorophores in ageand diabetes-related cross-linked proteins, and their diacetates produced by Maillard reaction of a-N-acetyl-L -lysine with D -glucose”, J. Chem. Soc., Chem. Commun., 992 –994. Neumann, A., Schinzel, R., Palm, D., Riederer, P. and Munch, G. (1999) “High molecular weight hyaluronic acid inhibits

207

advanced glycation endproduct-induced NF-kappa B activation and cytokine expression”, FEBS Lett. 453, 283–287. Niwa, T. and Tsukushi, S. (2001) “3-Deoxyglucosone and AGEs in uremic complications: inactivation of glutathione peroxidase by 3-deoxyglucosone”, Kidney Int. 59, S37–S41. Niwa, T., Sato, M., Katsuzaki, T., Tomoo, T., Miyazaki, T., Tatemichi, N., Takei, Y. and Kondo, T. (1996) “Amyloid beta(2)-microglobulin is modified with N-epsilon-(carboxymethyl)lysine in dialysis-related amyloidosis”, Kidney Int. 50, 1303–1309. Niwa, T., Katsuzaki, T., Miyazaki, S., Miyazaki, T., Ishizaki, Y., Hayase, F., Tatemichi, N. and Takei, Y. (1997a) “Immunohistochemical detection of imidazolone, a novel advanced glycation end product, in kidneys and aortas of diabetic patients”, J. Clin. Investig. 99, 1272–1280. Niwa, T., Katsuzaki, T., Miyazaki, S., Momoi, T., Akiba, T., Miyazaki, T., Nokura, K., Hayase, F., Tatemichi, N. and Takei, Y. (1997b) “Amyloid beta 2-microglobulin is modified with imidazolone, a novel advanced glycation end product, in dialysis-related amyloidosis”, Kidney Int. 51, 187 –194. Niwa, T., Katsuzaki, T., Miyazaki, S., Momoi, T., Akiba, T., Miyazaki, T., Nokura, K., Hayase, F., Tatemichi, N. and Takei, Y. (1997c) “Amyloid beta(2)-microglobulin is modified with imidazolone, a novel advanced glycation end product, in dialysis-related amyloidosis”, Kidney Int. 51, 187 –194. Niwa, H., Takeda, A., Wakai, M., Miyata, T., Yasuda, Y., Mitsuma, T., Kurokawa, K. and Sobue, G. (1998) “Accelerated formation of N epsilon-(carboxymethyl) lysine, an advanced glycation end product, by glyoxal and 3-deoxyglucosone in cultured rat sensory neurons”, Biochem. Biophys. Res. Commun. 248, 93 –97. Obayashi, H., Nakano, K., Shigeta, H., Yamaguchi, M., Yoshimori, K., Fukui, M., Fujii, M., Kitagawa, Y., Nakamura, N., Nakamura, K., Nakazawa, Y., Ienaga, K., Ohta, M., Nishimura, M., Fukui, I. and Kondo, M. (1996) “Formation of crossline as a fluorescent advanced glycation end product in vitro and in vivo”, Biochem. Biophys. Res. Commun. 226, 37 –41. Odani, H., Shinzato, T., Matsumoto, Y., Takai, I., Nakai, S., Miwa, M., Iwayama, N., Amano, I. and Maeda, K. (1996) “First evidence for accumulation of protein-bound and protein-free pyrraline in human uremic plasma by mass spectrometry”, Biochem. Biophys. Res. Commun. 224, 237–241. Odetti, P., Angelini, G., Dapino, D., Zaccheo, D., Garibaldi, S., Dagna-Bricarelli, F., Piombo, G., Perry, G., Smith, M., Traverso, N. and Tabaton, M. (1998a) “Early glycoxidation damage in brains from Down’s syndrome”, Biochem. Biophys. Res. Commun. 243, 849–851. Odetti, P., Angelini, G., Dapino, D., Zaccheo, D., Garibaldi, S., Dagna-Bricarelli, F., Piombo, G., Perry, G., Smith, M., Traverso, N. and Tabaton, M. (1998b) “Early glycoxidation damage in brains from Down’s syndrome”, Biochem. Biophys. Res. Commun. 243, 849–851. Odetti, P., Garibaldi, S., Norese, R., Angelini, G., Marinelli, L., Valentini, S., Menini, S., Traverso, N., Zaccheo, D., Siedlak, S., Perry, G., Smith, M.A. and Tabaton, M. (2000) “Lipoperoxidation is selectively involved in progressive supranuclear palsy”, J. Neuropathol. Exp. Neurol. 59, 393–397. Ohgami, N., Nagai, R., Nakayama, H., Ikemoto, M. and Horiuchi, S. (2000) “CD36, a member of class B scavenger receptor family, as a receptor for advanced glycation end products”, Diabetes 49, 312. Ohgami, N., Nagai, R., Ikemoto, M., Arai, H., Kuniyasu, A., Horiuchi, S. and Nakayama, H. (2001) “CD36, a member of the class B scavenger receptor family, as a receptor for advanced glycation end products”, J. Biol. Chem. 276, 3195–3202. Okamoto, G., Hayase, F. and Kato, H. (1992) “Scavenging of active oxygen species by glycated proteins”, Biosci., Biotechnol., Biochem. 56, 928–931. Pari, K., Sundari, C.S., Chandani, S. and Balasubramanian, D. (2000) “beta-Carbolines that accumulate in human tissues may serve a protective role against oxidative stress”, J. Biol. Chem. 275, 2455–2462. Pedersen, W.A., Cashman, N.R. and Mattson, M.P. (1999) “The lipid peroxidation product 4-hydroxynonenal impairs glutamate and glucose transport and choline acetyltransferase activity in NSC-19 motor neuron cells”, Exp. Neurol. 155, 1–10.

208

V. PRAKASH REDDY et al.

Perez, M., Cuadros, R., Smith, M.A., Perry, G. and Avila, J. (2000) “Phosphorylated, but not native, tau protein assembles following reaction with the lipid peroxidation product, 4-hydroxy-2-nonenal”, FEBS Lett. 486, 270–274. Perry, G., Nunomura, A. and Smith, M.A. (1999) “Antioxidant reversal of oxidative stress-induced memory deficits”, Neuroreport 10, I –I. Porretta, S. (1992) “Chromatographic analysis of Maillard reaction products”, J. Chromatogr. 624, 211–219. Porterootin, M., Nagaraj, R.H. and Monnier, V.M. (1995) “Chromatographic evidence for Pyrraline formation during protein glycation in-vitro and in-vivo”, Biochim. Biophys. Acta— Protein Struct. Molec. Enzym. 1247, 74–80. Rahbar, S., Kumar Yernini, K., Scott, S., Gonzales, N. and Lalezari, I. (1999) “Novel inhibitors of advanced glycation endproducts”, Biochem. Biophys. Res. Commun. 262, 651–656. Roberts, R.L. and Lloyd, R.V. (1997) “Free radical formation from secondary amines in the Maillard reaction”, J. Agric. Food Chem. 45, 2413– 2418. Roscic, M., Versluis, C., Kleinnijenhuis, A.J., Horvat, S. and Heck, A.J. (2001) “The early glycation products of the Maillard reaction: mass spectrometric characterization of novel imidazolidinones derived from an opioid pentapeptide and glucose”, Rapid Commun. Mass Spectrom. 15, 1022–1029. Rosler, M., Retz, W., Thome, J. and Riederer, P. (1998) “Free radicals in Alzheimer’s dementia: currently available therapeutic strategies”, J. Neural Transm., Suppl. 54, 211–219. Royle, L., Bailey, R.G. and Ames, J.M. (1998) “Separation of Maillard reaction products from xylose–glycine and glucose– glycine model systems by capillary electrophoresis and comparison to reverse phase HPLC”, Food Chem. 62, 425 –430. Saez-Valero, J. and Small, D.H. (2001) “Altered glycosylation of cerebrospinal fluid butyrylcholinesterase in Alzheimer’s disease”, Brain Res. 889, 247–250. Salinero, O., Moreno-Flores, M.T. and Wandosell, F. (2000) “Increasing neurite outgrowth capacity of b-amyloid precursor protein proteoglycan in Alzheimer ’s disease”, J. Neurosci. Res. 60, 87– 97. Sasaki, N., Toki, S., Chowei, H., Saito, T., Nakano, N., Hayashi, Y., Takeuchi, M. and Makita, Z. (2001) “Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer’s disease”, Brain Res. 888, 256 –262. Sato, Y., Naito, Y., Grundke-Iqbal, I., Iqbal, K. and Endo, T. (2001) “Analysis of N-glycans of pathological tau: possible occurrence of aberrant processing of tau in Alzheimer’s disease”, FEBS Lett. 496, 152– 160. Saxena, A.K., Saxena, P., Wu, X.L., Obrenovich, M., Weiss, M.F. and Monnier, V.M. (1999) “Protein aging by carboxymethylation of lysines generates sites for divalent metal and redox active copper binding: relevance to diseases of glycoxidative stress”, Biochem. Biophys. Res. Commun. 260, 332–338. Sayre, L.M., Zelasko, D.A., Harris, P.L.R., Perry, G., Salomon, R.G. and Smith, M.A. (1997) “4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease”, J. Neurochem. 68, 2092– 2097. Sayre, L.M., Smith, M.A. and Perry, G. (2001) “Chemistry and biochemistry of oxidative stress in neurodegenerative disease”, Curr. Med. Chem. 8, 721–738. Schippling, S., Kontush, A., Arlt, S., Buhmann, C., Sturenburg, H.J., Mann, U., Muller-Thomsen, T. and Beisiegel, U. (2000) “Increased lipoprotein oxidation in Alzheimer’s disease”, Free Radic. Biol. Med. 28, 351–360. Schmidt, A.M., Yan, S.D., Wautier, J.L. and Stern, D. (1999) “Activation of receptor for advanced glycation end products—a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis”, Circ. Res. 84, 489 –497. Schmidt, A.M., Yan, S.D., Yan, S.F. and Stern, D.M. (2000) “The biology of the receptor for advanced glycation end products and its ligands”, Biochim. Biophys. Acta—Mol. Cell Res. 1498, 99– 111. Seidl, R., Schuller, E., Cairns, N. and Lubec, G. (1997) “Evidence against increased glycoxidation in patients with Alzheimer’s disease”, Neurosci. Lett. 232, 49 –52. Sell, D.R. and Monnier, V.M. (1989) “Structure elucidation of a senescence cross-link from human extracellular matrix.

Implication of pentoses in the aging process”, J. Biol. Chem. 264, 21597– 21602. Sell, D.R., Nagaraj, R.H., Grandhee, S.K., Odetti, P., Lapolla, A., Fogarty, J. and Monnier, V.M. (1991) “Pentosidine: a molecular marker for the cumulative damage to proteins in diabetes, aging, and uremia”, Diabetes Metab. Rev. 7, 239 –251. Sell, D.R., Primc, M., Schafer, I.A., Kovach, M., Weiss, M.A. and Monnier, V.M. (1998) “Cell-associated pentosidine as a marker of aging in human diploid cells in vitro and in vivo”, Mech. Ageing Dev. 105, 221 –240. Shipanova, I.N., Glomb, M.A. and Nagaraj, R.H. (1997) “Protein modification by methylglyoxal: chemical nature and synthetic mechanism of a major fluorescent adduct”, Arch. Biochem. Biophys. 344, 29–36. Shoda, H., Miyata, S., Liu, B.F., Yamada, H., Ohara, T., Suzuki, K., Oimomi, M. and Kasuga, M. (1997) “Inhibitory effects of tenilsetam on the maillard reaction”, Endocrinology 138, 1886–1892. Shuvaev, V.V., Laffont, I., Serot, J.M., Fujii, J., Taniguchi, N. and Siest, G. (2001) “Increased protein glycation in cerebrospinal fluid of Alzheimer’s disease”, Neurobiol. Aging 22, 397–402. Singh, R., Barden, A., Mori, T. and Beilin, L. (2001) “Advanced glycation end-products: a review”, Diabetologia 44, 129–146. Smith, M.A., Richey, P.L., Taneda, S., Kutty, R.K., Sayre, L.M., Monnier, V.M. and Perry, G. (1994a) “Advanced Maillard reaction end-products. Free-radicals, and protein oxidation in Alzheimer’s-disease”, Annal. NY Acad. Sci. 738, 447–454. Smith, M.A., Taneda, S., Richey, P.L., Miyata, S., Yan, S.-D., Stern, D., Sayre, L.M., Monnier, V.M. and Perry, G. (1994b) “Advanced Maillard reaction end products are associated with Alzheimer disease pathology”, Proc. Natl Acad. Sci. USA 91, 5710–5714. Smith, M.A., Sayre, L.M., Vitek, M.P., Monnier, V.M. and Perry, G. (1995a) “Early aging and Alzheimers”, Nature 374, 316–316. Smith, M.A., Taneda, S., Richey, P.L., Miyata, S., Yan, S.D., Stern, D., Sayre, L.M., Monnier, V.M. and Perry, G. (1995b) “Advanced Maillard reaction end-products are associated with Alzheimer-disease pathology”, Proc. Natl Acad. Sci. USA 92, 1794–1794; and 91, 5710–5714. Smith, M.A., Sayre, L.M., Anderson, V.E., Harris, P.L.R., Beal, M.F., Kowall, N. and Perry, G. (1998) “Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4-dinitrophenylhydrazine”, J. Histochem. Cytochem. 46, 731–735. Sugimoto, H. (1999) “Structure –activity relationships of acetylcholinesterase inhibitors: donepezil hydrochloride for the treatment of Alzheimer’s disease”, Pure Appl. Chem. 71, 2031–2037. Tabaton, M., Perry, G., Smith, M., Vitek, M., Angelini, G., Dapino, D., Garibaldi, S., Zaccheo, D. and Odetti, P. (1997) “Is amyloid beta-protein glycated in Alzheimer’s disease?”, Neuroreport 8, 907 –909. Takahashi, M., Tsujioka, Y., Yamada, T., Tsuboi, Y., Okada, H., Yamamoto, T. and Liposits, Z. (1999) “Glycosylation of microtubule-associated protein tau in Alzheimer’s disease brain”, Acta Neuropathol. 97, 635–641. Takeda, A., Yasuda, T., Miyata, T., Goto, Y., Wakai, M., Watanabe, M., Yasuda, Y., Horie, K., Inagaki, T., Doyu, M., Maeda, K. and Sobue, G. (1998) “Advanced glycation end products colocalized with astrocytes and microglial cells in Alzheimer’s disease brain”, Acta Neuropathol. 95, 555–558. Takeda, A., Smith, M.A., Avila, J., Nunomura, A., Siedlak, S.L., Zhu, X.W., Perry, G. and Sayre, L.M. (2000) “In Alzheimer’s disease, heme oxygenase is coincident with Alz50, an epitope of tau induced by 4-hydroxy-2-nonenal modification”, J. Neurochem. 75, 1234–1241. Takeda, A., Wakai, M., Niwa, H., Dei, R., Yamamoto, M., Li, M., Goto, Y., Yasuda, T., Nakagomi, Y., Watanabe, M., Inagaki, T., Yasuda, Y., Miyata, T. and Sobue, G. (2001) “Neuronal and glial advanced glycation end product [N-epsilon-(carboxymethyl)lysine] in Alzheimer’s disease brains”, Acta Neuropathol. 101, 27–35. Takeuchi, M., Bucala, R., Suzuki, T., Ohkubo, T., Yamazaki, M., Koike, T., Kameda, Y. and Makita, Z. (2000) “Neurotoxicity of advanced glycation end-products for cultured cortical neurons”, J. Neuropathol. Exp. Neurol. 59, 1094–1105.

MAILLARD REACTIONS AND ALZHEIMER DISEASE Tessier, F., Obrenovich, M. and Monnier, V.M. (1999) “Structure and mechanism of formation of human lens fluorophore LM1—relationship to vesperlysine A and the advanced Maillard reaction in aging, diabetes, and cataractogenesis”, J. Biol. Chem. 274, 20796– 20804. Thorpe, S.R. and Baynes, J.W. (1996) “Role of the maillard reaction in diabetes mellitus and diseases of aging”, Drugs Aging 9, 69– 77. Tomlinson, A.J., Landers, J.P., Lewis, I.A.S. and Naylor, S. (1993) “Buffer conditions affecting the separation of Maillard reaction products by capillary electrophoresis”, J. Chromatogr. 652, 171–177. Uesugi, N., Sakata, N., Nagai, R., Jono, T., Horiuchi, S. and Takebayashi, S. (2000) “Glycoxidative modification of AA amyloid deposits in renal tissue”, Nephrol. Dial. Transplant. 15, 355– 365. Ulrich, P. and Cerami, A. (2001) “Protein glycation, diabetes, and aging”, Recent Prog. Horm. Res. 56, 1–21. Vitek, M.P., Bhattacharya, K., Glendening, J.M., Stopa, E., Vlassara, H., Bucala, R., Manogue, K. and Cerami, A. (1994) “Advanced glycation end products contribute to amyloidosis in Alzheimer disease”, Proc. Natl Acad. Sci. USA 91, 4766–4770. Vlassara, H., Bucala, R. and Striker, L. (1994) “Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging”, Lab. Investig. 70, 138– 151. Wang, J.Z., Gong, C.X., Zaidi, T., Grundke-Iqbal, I. and Iqbal, K. (1995) “Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B”, J. Biol. Chem. 270, 4854–4860. Wang, J.-Z., Grundke-Iqbal, I. and Iqbal, K. (1996a) “Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease”, Nat. Med. (NY) 2, 871– 875. Wang, J.-Z., Grundke-Iqbal, I. and Iqbal, K. (1996b) “Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1”, Mol. Brain Res. 38, 200–208. Wang, M., Jin, Y., Li, J. and Ho, C.-T. (1999) “Two novel b-Carboline compounds from the Maillard reaction between Xylose and Tryptophan”, J. Agric. Food Chem. 47, 48 –50. Weber, K., Schmahl, W. and Munch, G. (1998) “Distribution of advanced glycation end products in the cerebellar neurons of dogs”, Brain Res. 791, 11–17. Wilker, S.C., Chellan, P., Arnold, B.M. and Nagaraj, R.H. (2001) “Chromatographic quantification of argpyrimidine, a methylglyoxal-derived product in tissue proteins: comparison with pentosidine”, Anal. Biochem. 290, 353 –358.

209

Wolffenbuttel, B.H.R., Boulanger, C.M., Crijns, F.R.L., Huijberts, M.S.P., Poitevin, P., Swennen, G.N.M., Vasan, S., Egan, J.J., Ulrich, P., Cerami, A. and Levy, B.I. (1998a) “Breakers of advanced glycation end products restore large artery properties in experimental diabetes”, Proc. Natl Acad. Sci. USA 95, 4630–4634. Wolffenbuttel, B.H.R., Boulanger, C.M., Crijns, F.R.L., Poitevin, P., Egan, J.J., Cerami, A. and Levy, B.I. (1998b) “ALT-711, a breaker of advanced glycation endproducts (AGEs), restores large artery elasticity in experimental diabetes”, Diabetes 47, 88. Yamaguchi, M., Nakamura, N., Nakano, K., Kitagawa, Y., Shigeta, H., Hasegawa, G., Ienaga, K., Nakamura, K., Nakazawa, Y., Fukui, I., Obayashi, H. and Kondo, M. (1998) “Immunochemical quantification of crossline as a fluorescent advanced glycation endproduct in erythrocyte membrane proteins from diabetic patients with or without retinopathy”, Diabetic Med. 15, 458–462. Yan, S.D., Chen, X., Schmidt, A.M., Brett, J., Godman, G., Zou, Y.S., Scott, C.W., Caputo, C., Frappier, T., Smith, M.A., Perry, G., Yen, S.H. and Stern, D. (1994) “Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress”, Proc. Natl Acad. Sci. USA 91, 7787– 7791. Yan, S.D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., Migheli, A., Nawroth, P., Stern, D. and Schmidt, A.M. (1996) “RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease”, Nature 382, 685 –691. Yan, S.D., Fu, J., Soto, C., Chen, X., Zhu, H.J., Almohanna, F., Collison, K., Zhu, A.P., Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A. and Stern, D. (1997) “An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer’s disease”, Nature 389, 689 –695. Yan, S.D., Stern, D., Kane, M.D., Kuo, Y.M., Lampert, H.C. and Roher, A.E. (1998) “RAGE—a beta interactions in the pathophysiology of Alzheimer’s disease”, Restor. Neurol. Neurosci. 12, 167–173. Yan, S.D., Roher, A., Chaney, M., Zlokovic, B., Schmidt, A.M. and Stern, D. (2000) “Cellular cofactors potentiating induction of stress and cytotoxicity by amyloid beta-peptide”, Biochim. Biophys. Acta-Mol. Basis Dis. 1502, 145–157. Yoshimura, Y., Iijima, T., Watanabe, T. and Nakazawa, H. (1997) “Antioxidative effect of Maillard reaction products using glucose–glycine model system”, J. Agric. Food Chem. 45, 4106–4109. Zyzak, D.V., Richardson, J.M., Thorpe, S.R. and Baynes, J.W. (1995) “Formation of reactive intermediates from Amadori compounds under physiological Conditions”, Arch. Biochem. Biophys. 316, 547–554.