Abstract
Although the aggregation process of amyloidogenic proteins has been widely studied in vitro and many physiological factors have been identified, the molecular mechanisms underlying the formation of aggregates in vivo and under pathological conditions are still poorly understood. Post‐translational modifications are known to affect protein structure and function. Some of these modifications might affect proteins in detrimental ways and lead to their misfolding and accumulation. Reducing sugars play an important role in modifying proteins, forming advanced glycation end‐products (AGEs) in a nonenzymatic process, called glycation. Recently, much attention has been devoted to the role played by glycation in stimulating amyloid aggregation and cellular toxicity. Proteins in amyloid deposits are often found glycated, suggesting a direct correlation between protein glycation and amyloidosis.
Keywords
- amyloid aggregation
- protein glycation
- AGEs
- cellular toxicity
1. Introduction
Reducing sugars play an important role in modifying proteins, forming advanced glycation end‐products (AGEs) in a nonenzymatic process, called glycation. This process is different from glycosylation; indeed, these two post‐translational modifications affect the structure of the target protein in a different way. Glycosylation is a selective protein modification, driven by specific enzymes, that is generally associated with a gain of function (or stabilization) of the target protein. Nonenzymatic glycation is a nonselective modification, and it is generally associated with a loss of function of the target protein due to modifications of its native structure. While glycosylation is a well‐controlled cellular mechanism, nonenzymatic glycation depends on the exposure of free amino groups in the polypeptide chain, concentration of the sugar, and oxidative conditions. Glycation is a pathological process that is highly relevant in diabetes patients, as it plays a crucial role not only in diabetic complications but also in the normal aging process. Increasing evidence suggests a link between diabetes and neurodegenerative processes such as Alzheimer and Parkinson diseases [1]. In this respect, much attention has been recently devoted to the role played by nonenzymatic glycation of proteins in stimulating amyloid aggregation and toxicity. The observation that proteins in amyloid deposits, such as
Moreover, the AGE‐modified proteins are tightly involved in physiopathological cellular mechanisms. Once formed, AGEs interact with specific cellular receptors leading to the activation of different signaling pathways. The most studied AGE‐receptor, known as RAGE, is a multiligand receptor belonging to the immunoglobulin superfamily [13, 14]. The activation of RAGE regulates key cellular processes such as inflammation, apoptosis, proliferation, autophagy, and recently it has been associated with the pathogenesis of amyloidosis [15, 16]. In neurons, glia, and endothelial cells, RAGE is also the binding site for A
2. Protein glycation
The nonenzymatic glycation of protein amino groups by reducing sugars (also called Maillard reaction) is a chemical reaction common to all cell types: glycated products slowly accumulate in vivo, leading to several different protein dysfunctions caused by alterations of their integrity [19, 20]. The process begins with a nucleophilic addition reaction between a free amino group of a protein and a carbonyl group of a reducing sugar, forming a reversible intermediate product (Schiff's base). Side‐chains of arginine and lysine residues and the N‐terminal amino group of proteins are the main targets of protein glycation. The process depends on several conditions, such as the concentration and reactivity of the glycation agent, the presence of catalytic factors (metals, buffer ions, and oxygen), the physiological pH, temperature, and the half‐life of each protein. All reducing sugars can participate in glycation reactions and, among them, D‐ribose is the most active form, and its intracellular level can be quite high. D‐glucose is the less reactive form and its intracellular concentration is negligible, while dicarbonyl compounds, such as methylglyoxal and glyoxal, are far more reactive. These compounds are intermediates of glycation reaction, but can also be generated by various oxidative processes and be formed through other metabolic pathways such as glycolysis and catabolism of threonine and ketone bodies. The levels of D‐ribose in the blood are estimated around 20 mg/L in healthy individuals, while that of D‐glucose are around 6–10 g/L. Once formed, the Schiff's base can convert into a stable ketoamine by Amadori rearrangement (Figure 1). This reaction is reversible, depending on the concentration of the reactants. The late stage of the process is an irreversible cascade of reactions involving enolization, dehydration, condensation, oxidation, fragmentation, and other rearrangements, leading to the formation of AGEs [21]. Glucose, Schiff's base, and Amadori product, can also exhibit auto‐oxidation reactions that are responsible for free radicals and highly reactive carbonyl compound production. These compounds can react with other amino acid side‐chains and further contribute to post‐translational modifications. Unlike organic syntheses, AGEs formation does not produce well‐defined products but a large number of structures. The pathways leading to several AGEs are extensively outlined in [22]. Glycation reaction produces very reactive intermediates that can promote the formation of intramolecular and intermolecular cross‐links within AGE‐modified protein monomers. However, the reaction can also evolve into AGE protein adducts unable to form covalent cross‐links (Figure 1).
3. Differential effects of glycation on protein aggregation and cytotoxicity
Several proteins related and not related to misfolding diseases have been so far examined to investigate the effect of glycation on their propensity to aggregate and form amyloid structure.
3.1. Proteins related to misfolding diseases
3.1.1. Aβ ‐peptide
A
A
3.1.2. β 2‐Microglobulin
Glycation seems to promote amyloid aggregation in
3.1.3. Insulin
Insulin is a small protein hormone that is crucial for the control of glucose metabolism. Monomeric insulin undergoes amyloid aggregation in vivo, and insulin amyloid‐like fibrils are the hallmark of a clinical condition observed in insulin‐dependent diabetic patients, called insulin injection amyloidosis.
Glycation of insulin has been reported to differentially affect protein structure, stability, and aggregation, depending on the glycating agent and/or environmental conditions. This protein is intimately associated with glycemia and is vulnerable to glycation by glucose and other highly reactive carbonyls, especially in diabetic conditions [43]. Glycated insulin is unable to regulate glucose homeostasis in vivo and to stimulate glucose transport and adipose tissue lipogenesis [44].
In vitro experiments have shown that insulin can be glycated by glucose to be able to react with Lys29 in the C‐terminal region of chain B and with N‐terminus of chains A and B [45, 46]. Glucose induces the formation of glycated insulin adducts having different structural features, depending on the experimental conditions used. In particular, glycation in reducing conditions is able to induce insulin oligomerization, thus accelerating amyloid formation. On the contrary, glycation in nonreducing conditions strongly inhibit amyloid formation in a way proportional to the glycation extent [47]. Probably, under the latter conditions, insulin adducts possess a higher internal dynamics that prevent formation of the rigid cross‐
3.1.4. α ‐Synuclein
In vitro studies showed that AGEs promote cross‐linking of
Choi and Lim [60] reported, in a mouse model of parkinsonism, that
These results indicate that glycation of
3.1.5. Lysozime
Hen egg white lysozyme (HEWL) has also been used to study the impact of glycation on protein structure and aggregation. HEWL is a structural homolog of human lysozyme, responsible for systemic amyloidosis disease and, for this reason, it is considered a very good model for amyloid aggregation studies. HEWL undergoes glycation in vitro, and potential glycation sites are considered to be the N‐terminal
3.2. Proteins not related to misfolding diseases
3.2.1. Albumin
Human serum albumin (HSA) is the most abundant protein in human plasma or serum (around 60% of total proteins). Serum albumin is known to be capable of self‐assembling in amyloidogenic aggregates under particular experimental conditions (pH, temperature, concentration, and isoelectric point) and is a widely used model for the study of amyloid aggregation. Both HSA and bovine serum albumin (BSA) have been shown to be efficiently glycated in vitro by different glycating agents. Glycation and AGE modifications of serum albumin induce structural changes that depend on the chemical reactivity of the modifying reagent and the concentration used for in vitro glycation. However, glycation has been shown to promote strong conformational changes affecting both secondary and tertiary structures. Such modifications in tertiary structure have been revealed by complementary spectroscopical techniques: circular dichroism (CD), Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR), and fluorescence spectroscopy [65–69]. In particular, the microenvironment of Trp214 seems to be strongly affected by glycation as indicated by fluorescence and NMR spectroscopy [66, 69]. Such conformational changes in the tertiary structure could be a consequence of molecular rearrangements after the formation of AGE products. Indeed, some of these AGEs forming covalent cross‐links within adjacent protein strands require conformational changes which produce more apolar and tight molecules with respect to the native protein. Besides, the accessibility of the hydrophobic regions in the protein has been shown to increase with glycation [67, 68]. Modification at the secondary structure level can be detected only at longer times of incubation with glycating agents. This could be due to the fact that glycation is likely to induce loss of tertiary structure before that of secondary structure, as suggested by comparing intrinsic fluorescence and far‐UV CD results in glycated albumin [65, 66, 70].
Glycation‐induced protein misfolding promotes the formation of amyloid‐like aggregates in serum albumin [12, 71, 72]. These amyloid‐like deposits appear as densely staining granules under atomic force microscopy and are able to bind the amyloid‐specific dye thioflavin T. Also, they were shown to induce high cytotoxicity that triggers cell death by activation of cellular signaling cascades. In fact, independent experiments have shown that aggregates of glycated BSA are able to induce ROS‐mediated oxidative stress and apoptosis in both neurotypic SH‐SY5Y and MCF‐7 cells. These results indicate that glycation of serum albumin results in the formation of oligomeric or globular structures that are the more toxic aggregate forms [68, 72].
These observations could have important implications, as serum albumin, being a circulating protein, is likely undergoing glycative alteration in the case of diabetes pathology and hyperglycemia. For instance, antioxidant activities of serum albumin were impaired in patients with diabetes.
3.2.2. Apomyoglobin
Apomyoglobin (i.e., heme‐free myoglobin) is a small, soluble
Wild‐type apomyoglobin is rapidly glycated in vitro by different glycating agents, and glycation has been shown to induce strong conformational changes, affecting both secondary and tertiary structures. In particular, glycation induces partial loss of the helical content in apomyoglobin without promoting an
At the same time, glycation has been shown to affect the aggregation kinetics in the W7FW14F apomyoglobin mutant, able to form amyloid fibrils in physiological conditions [73–78]. In particular, glycation accelerates the formation of harmless amyloid fibrils in the apomyoglobin this amyloidogenic mutant [76]. A plausible explanation for such faster kinetics could be related to a higher tendency of the mutant to form intermolecular links upon glycation able to reduce the flexibility of aggregation‐prone regions and thus favor the subsequent step of fibril elongation.
Although apomyoglobin is not related to any amyloidogenic diseases, it represents a suitable model for studying the role of glycation in amyloid aggregation. Indeed, due to the different aggregation propensities of the native protein and the W7FW14F mutant in physiological conditions, this protein model allows to dissect the effect of glycation in promoting amyloid aggregation and contributes to the aggregation kinetics. The above results indicate that glycation can be considered not only a triggering factor in amyloidosis but also a player in later stages of the aggregation process.
4. Molecular effects of glycation on amyloid aggregation process
The overall evidences on several model proteins indicate that AGE modifications may alter the folding state of proteins and their solubility, thereby influencing protein aggregation. The main outcome of this study is that the effect of glycation on amyloid aggregation cannot be generalized. Indeed, being a post‐translational modification, it differentially affects the aggregation process in proteins by promoting, accelerating, and/or stabilizing on‐pathway and off‐pathway species (Figure 2). Molecular basis of such modulation are still poorly understood. Most of the evidence indicate that glycation strongly affects the tertiary structure of the target protein promoting the formation of globular amyloid‐like deposits [62, 72]. Depending on the protein involved, glycation induces chemical modifications of the positively charged side chains (mostly lysine, arginine, and N‐terminus), thus affecting the protein charge and favoring the exposure of its hydrophobic surface. This effect could trigger native‐like aggregation favoring the formation of small oligomers that, being stabilized by the AGE‐derived covalent cross‐links, do not evolve into amyloid fibrils. Recent evidence indicates that glycation promotes the formation of the amyloid oligomeric species in several model proteins (Figure 2B). However, glycation does not necessarily induce protein oligomerization. Due to the complexity of the glycation reaction, some AGE adducts might not evolve to the formation of protein cross‐links. In this case, glycation seems to stabilize the monomeric form thus inhibiting the amyloid aggregation process as observed for ribosylated human insulin (Figure 2C). Moreover, the cross‐links of AGE‐derived oligomers do not necessarily show amyloid properties (Figure 2D). However, AGEs‐modified proteins are always able to affect cell viability, irrespective of amyloid properties.
5. Role of glycation in the amyloid‐induced cell toxicity
The effect of glycation on the aggregation process has important implications in the pathological mechanisms involved in amyloid diseases. In most proteins, glycation has been shown to stabilize the aggregates in the oligomeric forms. This modification has important pathological implications as oligomeric species are known to be far more toxic than the fibrillar aggregates [80, 81]. The oligomeric species may interact with the cell membrane, altering its permeability and leading to cell homeostasis imbalance and neuronal cell dysfunction [82]. Recent evidence indicates that the amyloid oligomer toxicity is not strictly related to the oligomer properties, but rather a behavior that results from a complex interplay between the structural properties of both oligomers and cell membrane taken as a whole. Indeed, oligomers of comparable size but different structure and biophysical properties can display different toxicities, possibly as a consequence of the increased exposure of hydrophobic residues that would destabilize them and favor the interaction with the plasma membrane [83]. In this respect, glycation could affect structural and physicochemical features of amyloid oligomers as well as their interaction to the cell membrane and subsequently modulate and/or induce the cell toxicity. Also, the glycated oligomeric species can induce formation of reactive oxygen species, worsening the oxidative stress in the cell and further promoting protein glycation. Moreover, protein glycation leads to the formation of AGEs which have a pathological role in several diseases [84–86]. AGE adducts may therefore activate, through interaction with RAGE receptor, inflammatory response generally associated to amyloid toxicity [13]. The AGE–RAGE binding results in the activation of NADPH‐oxidases that leads to an increased production of ROS. A key downstream target of RAGE is the proinflammatory Nf‐κB pathway, which in turn leads to high RAGE expression, producing a feedback loop in which continuous activation of RAGE keeps the cellular inflammatory state activated [14, 87].
Glycated proteins are also resistant to proteasomal degradation; once proteins become glycated at their exposed lysine residues, clearance by the ubiquitin–proteasome system would be impaired, because ubiquitination at lysine residues, a modification that targets proteins to the proteasome for degradation, might be impeded. Thus, accumulation of proteins as aggregates or as depositions or inclusions in tissues might be favored after glycation.
Taking into account the above considerations, protein glycation can be considered a key dynamic contributor to these multifactorial diseases. In fact, it can both promote the formation of pathological oligomeric species and directly trigger cell dysfunction, damage, and death through the AGEs formation. For these reasons, AGEs are considered key therapeutic targets in amyloidosis, and anti‐AGEs drugs are objects of intense ongoing research. Specifically, three main strategies have been developed to counteract the AGEs’ effects: (i) to prevent the formation of AGEs; (ii) to break cross‐links after their formation; (iii) to prevent AGEs’ negative effects.
In vitro and in vivo experiments have shown that many compounds including aminoguanidine, antioxidants such as vitamin C and vitamin E, pyridoxamine, thiamine and its synthetic derivative benfotiamine, alpha‐lipoic acid, taurine, pimagedine, aspirin, carnosine, metformin, pioglitazone, and pentoxifylline are able to inhibit AGE formation. Some of these compounds have already been used in clinical practice and some others are under clinical trials. Compounds that have been shown to break existing AGE cross‐links mainly include alagebrium (and related ALT‐462, ALT‐486, and ALT‐946) and N‐phenacylthiazolium bromide. Studies with the aim to counteract the negative effects of the AGEs mainly involve the use of natural products as polyphenols, such as resveratrol and curcumin and some flavonoids [88–90].
However, although in vitro and in vivo studies have shown the beneficial effects of various coumpounds, the potential clinical value of these interventions remains to be established. In fact, it seems that safety and/or efficacy in clinical studies with these compounds are still a concern.
References
- 1.
Hassan M, Sehgal SA, Rashid S. Regulatory cascade of neuronal loss and glucose metabolism. CNS Neurol Disord Drug Targets. 2014; 13(7) , 1232–45. - 2.
Miyata T, Oda O, Inagi R, Iida Y, Araki N, Yamada N, Horiuchi S, Taniguchi N, Maeda K, Kinoshita T. Beta 2‐microglobulin modified with advanced glycation end products is a major component of hemodialysis‐associated amyloidosis. J Clin Invest. 1993; 92 , 1243–52. - 3.
Ledesma MD, Bonay P, Colaco C, Avila J. Analysis of microtubule‐associated protein tau glycation in paired helical filaments. J Biol Chem. 1994; 269(34) , 21614–19. - 4.
Sasaki N, Fukatsu R, Tsuzuki K, Hayashi Y, Yoshida T, Fujii N, Koike T, Wakayama I, Yanagihara R, Garruto R, Amano N, Makita Z. Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. Am J Pathol. 1998; 153 , 1149–55. - 5.
Kikuchi S, Ogata A, Shinpo K, Moriwaka F, Fujii F, Taniguchi N, Tashiro K. Detection of an Amadori product, 1‐hexitol‐lysine, in the anterior horn of the amyotrophic lateral sclerosis and spinobulbar muscular atrophy spinal cord: evidence for early involvement of glycation in motoneuron diseases. Acta Neuropathol. 2000; 99 , 63–6. doi: 10.1007/PL00007407. - 6.
Munch G, Luth HJ, Wong A, Arendt T, Hirsch E, Ravid R, Riederer P. Crosslinking of alpha‐synuclein by advanced glycation endproducts–an early pathophysiological step in Lewy body formation? J Chem Neuroanat. 2000; 20 , 253–7. - 7.
Dukic‐Stefanovic S, Schinzel R, Riederer P, Munch G. AGES in brainageing: AGE‐inhibitors as neuroprotective and anti‐dementia drugs? Biogerontology. 2001; 2 , 19–34. doi: 10.1023/A:1010052800347. - 8.
Gomes R, Sousa Silva M, Quintas A, Cordeiro C, Freire A, Pereira P, Martins A, Monteiro E, Barroso E, Ponces Freire A. Argpyrimidine, a methylglyoxal‐derived advanced glycation end‐product in familial amyloidotic polyneuropathy. Biochem J . 2005;385 , 339–45. - 9.
Höhn A, Jung T, Grune T. Pathophysiological importance of aggregated damaged proteins. Free Radic Biol Med. 2014; 71 , 70–89. doi: 10.1016/j.freeradbiomed.2014.02.028. - 10.
Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, Bucala R, Manogue K, Cerami A. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci USA. 1994; 91 , 4766–70. doi: 10.1073/pnas.91.11.4766. - 11.
Chellan P, Nagaraj RH. Protein crosslinking by the Maillard reaction: dicarbonyl‐derived imidazolium crosslinks in aging and diabetes. Arch Biochem Biophys. 1999; 368 , 98–104. doi: 10.1006/abbi.1999.1291. - 12.
Bouma B, Kroon‐Batenburg LM, Wu YP, Brunjes B, Posthuma G, Kranenburg O, De Groot PG, Voest EE, Gebbink MF. Glycation induces formation of amyloid cross‐beta structure in albumin. J Biol Chem. 2003; 278 , 41810–9. doi: 10.1074/jbc.M303925200. - 13.
Xie J, Méndez JD, Méndez‐Valenzuela V, Aguilar‐Hernández MM. Cellular signalling of the receptor for advanced glycation end products (RAGE). Cell Signal. 2013; 25(11) , 2185–97. doi: 10.1016/j.cellsig.2013.06.013. - 14.
Ott C, Jacobs K, Haucke E, Santos AN, Grune N, Simm A. Role of advanced glycation end products in cellular signaling. Redox Biol. 2014; 2 , 411–29. doi: 10.1016/j.redox.2013.12.016. - 15.
Lue LF, Yan SD, Stern DM, Walker DG. Preventing activation of receptor for advanced glycation endproducts in Alzheimer's disease. Curr Drug Targets CNS Neurol Disord. 2005; 4(3) , 249–66. - 16.
Vicente Miranda H, Outeiro TF. The sour side of neurodegenerative disorders: the effects of protein glycation. J Pathol. 2010; 221(1) , 13–25. doi: 10.1002/path.2682. - 17.
Wan W, Chen H, Li Y. The potential mechanisms of Aβ‐receptor for advanced glycation end‐products interaction disrupting tight junctions of the blood‐brain barrier in Alzheimer's disease. Int J Neurosci. 2014; 124(2) , 75–81. doi: 10.3109/00207454.2013.825258. - 18.
Galasko D, Bell J, Mancuso JY, Kupiec JW, Sabbagh MN, van Dyck C, Thomas RG, Aisen PS; Alzheimer’s Disease Cooperative Study. Clinical trial of an inhibitor of RAGE‐Aβ interactions in Alzheimer disease. Neurology. 2014; 82(17) , 1536–42. doi: 10.1212/WNL.0000000000000364. - 19.
Miyata T, van Ypersele de Strihou C, Kurokawa K, Baynes JW. Alterations in nonenzymatic biochemistry in uremia: origin and significance of “carbonyl stress” in long‐term uremic complications. Kidney Int. 1999; 55 , 389–99. doi: 10.1046/j.1523‐1755.1999.00302.x. - 20.
Gul A, Rahman MA, Salim A, Simjee SU. Advanced glycation end products in senile diabetic and nondiabetic patients with cataract. J Diabetes Complications. 2009; 23 , 343–8. doi: 10.1016/j.jdiacomp.2008.04.001. - 21.
Ulrich P, Cerami A. Protein glycation, diabetes, and aging. Recent Prog Horm Res. 2001; 56 , 1–2. - 22.
Cho SJ, Roman G, Yeboah F, Konishi Y. The road to advanced glycation end products: a mechanistic perspective. Curr Med Chem. 2007; 14(15) , 1653–71. - 23.
Glomb MA, Monnier VM. Mechanism of protein modification by glyoxal and glycolaldehyde reactive intermediates of the Maillard reaction. J Biol Chem. 1995; 270 , 10017–26. - 24.
Münch G, Thome J, Foley P, Schinzel R, Riederer P. Advanced glycation end products in ageing and Alzheimer's disease. Brain Res Brain Res Rev. 1997; 23 , 134–143. - 25.
Münch G, Schinzel R, Loske C, Wong A, Durany N, Li JJ, Vlassara H, Smith MA, Perry G, Riederer P. Alzheimer's disease––synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts. J Neural Transm. 1998; 105 , 439–461. - 26.
Münch G, Deuther‐Conrad W, Gasic‐Milenkovic J. Glycoxidative stress creates a vicious cycle of neurodegeneration in Alzheimer's disease––a target for neuroprotective treatment strategies? J Neural Transm Suppl. 2002; 62 , 303–307. - 27.
Smith MA, Taneda S, Richey PL, Miyata S, Yan SD, Stern D, Sayre LM, Monnier VM, Perry G. Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl Acad Sci USA. 1994; 91(12) , 5710–4. - 28.
Münch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Müller R, Neumann A, Schinzel R, Cunningham AM. Influence of advanced glycation end‐products and AGEinhibitors on nucleation‐dependent polymerization of β‐amyloid peptide. Biochim Biophys Acta. 1997; 1360 , 17–29. - 29.
Fernandez‐Busquets X, Ponce J, Bravo R, Arimon M, Martianez T, Gella A, Cladera J, Durany N. Modulation of amylois β peptide 1‐42 cytotoxicity and aggregation in vitro by glucose and chondroitin sulfate. Curr Alzheimer Res. 2010; 7 , 428–38. doi: 10.2174/156720510791383787. - 30.
Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW. Neurodegeneration induced by beta‐amyloid peptides in vitro: the role of peptide assembly state. J Neurosci. 1993; 13 , 1676–87. - 31.
Dahlgren KN, Manelli AM, Stine WB Jr, Baker LK, Krafft GA, LaDu MJ. Oligomeric and fibrillar species of amyloid‐beta peptides differentially affect neuronal viability. J Biol Chem. 2002; 277(35) , 32046–53. - 32.
Chromy BA, Nowak RJ, Lambert MP, Viola KL, Chang L, Velasco PT, Jones BW, Fernandez SJ, Lacor PN, Horowitz P, Finch CE, Krafft GA, Klein WL. Self‐assembly of Abeta(1‐42) into globular neurotoxins. Biochemistry. 2003; 42(44) , 12749–60. - 33.
Sakono M, Zako T. Amyloid oligomers: formation and toxicity of Abeta oligomers. FEBS J. 2010; 277(6) , 1348–58. doi: 10.1111/j.1742‐4658.2010.07568.x. - 34.
Ladiwala AR, Litt J, Kane RS, Aucoin DS, Smith SO, Ranjan S, Davis J, Van Nostrand WE, Tessier PM. Conformational differences between two amyloid β oligomers of similar size and dissimilar toxicity. J Biol Chem. 2012; 287(29) , 24765–73. doi: 10.1074/jbc.M111.329763. - 35.
Stefani M. Structural polymorphism of amyloid oligomers and fibrils underlies different fibrillization pathways: immunogenicity and cytotoxicity. Curr Protein Pept Sci. 2010; 11(5) , 343–54. - 36.
Chen K, Maley J, Yu PH. Potential implications of endogenous aldehydes in beta‐amyloid misfolding, oligomerization and fibrillogenesis. J Neurochem. 2006; 99 , 1413–24. doi: 10.1111/j.1471‐4159.2006.04181.x. - 37.
Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM. RAGE and amyloid‐beta peptide neurotoxicity in Alzheimer's disease. Nature. 1996; 382 , 685–91. - 38.
Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE‐mediated signaling contributes to intraneuronal transport of amyloid‐beta and neuronal dysfunction. Proc Natl Acad Sci USA. 2009; 106 , 20021–6. - 39.
Hadding A, Kaltschmidt B, Kaltschmidt C. Overexpression of receptor of advanced glycation end products hypersensitizes cells for amyloid beta peptide‐induced cell death. Biochimica et Biophysica Acta. 2004; 169 1, 67–72. - 40.
Li XH, Du LL, Cheng XS, Jiang X, Zhang Y, Lv BL, Liu R, Wang JZ, Zhou XW. Glycation exacerbates the neuronal toxicity of β‐amyloid. Cell Death Dis. 2013; 4 , e673. doi: 10.1038/cddis.2013.180. - 41.
Kong FL, Cheng W, Chen J, Liang Y. D‐Ribose glycates b2‐microglobulin to form aggregates with high cytotoxicity through a ROS‐mediated pathway. Chem Biol Interact. 2011; 194 , 69–78. doi: 10.1016/j.cbi.2011.08.003. - 42.
Hashimoto N, Naiki H, Gejyo F. Modification of beta 2‐microglobulin with D‐glucose or 3‐deoxyglucosone inhibits A beta 2M amyloid fibril extension in vitro. Amyloid. 1999; 6 , 256–64. doi: 10.3109/13506129909007337. - 43.
Brange J, Andersen L, Laursen ED, Meyn G, Rasmussen E. Toward understanding insulin fibrillation. J Pharm Sci. 1997; 86 , 517–25. doi: 10.1021/js960297s. - 44.
Boyd AC, Abdel‐Wahab YH, McKillop AM, McNulty H, Barnett CR, O'Harte FP, Flatt PR. Impaired ability of glycated insulin to regulate plasma glucose and stimulate glucose transport and metabolism in mouse abdominal muscle. Biochim Biophys Acta. 2000; 1523(1) , 128–34. - 45.
O’Harte FPM, Højrup P, Barnett CR, Flatt PR. Identification of the site of glycation of human insulin. Peptides. 1996; 17 , 1323–30. - 46.
Guedes S, Vitorino R, Domingues MR, Amado F, Domingues P. Mass spectrometry characterization of the glycation sites of bovine insulin by tandem mass spectrometry. J Am Soc Mass Spectrom. 2009; 20 , 1319–26. doi: 10.1016/j.jasms.2009.03.004. - 47.
Alavi P, Yousefi R, Amirghofran S, Karbalaei‐Heidari HR, Moosavi‐Movahedi AA. Structural analysis and aggregation propensity of reduced and nonreduced glycated insulin adducts. Appl Biochem Biotechnol. 2013; 170 , 623–38. doi: 10.1016/j.ijbiomac.2012.05.021. - 48.
Oliveira LM, Lages A, Gomes RA, Neves H, Família C, Coelho AV, Quintas A. Insulin glycation by methylglyoxal results in native‐like aggregation and inhibition of fibril formation. BMC Biochem. 2011; 12 , 41. doi: 10.1186/1471‐2091‐12‐41. - 49.
Iannuzzi C, Borriello M, Carafa V, Altucci L, Vitiello M, Balestrieri ML, Ricci G, Irace G, Sirangelo I. D‐ribose‐glycation of insulin prevents amyloid aggregation and produces cytotoxic adducts. Biochim Biophys Acta. 2016; 1862(1) , 93–104. doi: 10.1016/j.bbadis.2015.10.021. - 50.
Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E. Oxidative stress induces amyloid‐like aggregate formation of NACP/α‐synuclein in vitro. Neuro Report. 1999; 10 , 717–21. - 51.
Paik SR, Shin HJ, Lee JH. Metal catalyzed oxidation of α‐synuclein in the presence of copper (II) and hydrogen peroxide. Arch Biochem Biophys. 2000; 378 , 269–77. - 52.
Guerrero E, Vasudevaraju P, Hegde ML, Britton GB, Rao KS. Recent advances in α‐synuclein functions, advanced glycation, and toxicity: implications for Parkinson's disease. Mol Neurobiol. 2013: 47(2) , 525–36. - 53.
Castellani R, Smith MA, Richey PL, Perry G. Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease. Brain Res. 1996; 737 : 195–200. - 54.
Dalfo E, Portero‐Otin M, Ayala V, Martinez A, Pamplona R, Ferrer I. Evidence of oxidative stress in the neocortex in incidental Lewy body disease. J Neuropathol Exp Neurol. 2005; 64 : 816–30. - 55.
Castellani RJ, Perry G, Siedlak SL, Nunomura A, Shimohama S, Zhang J, Montine T, Sayre LM, Smith MA. Hydroxynonenal adducts indicate a role for lipid peroxidation in neocortical and brainstem Lewy bodies in humans. Neurosci Lett. 2002; 319 , 25e28. - 56.
Shaikh S, Nicholson LF. Advanced glycation end products induce in vitro cross‐linking of alpha‐synuclein and accelerate the process of intracellular inclusion body formation. J Neurosci Res. 2008; 86 , 2071–82. - 57.
Lee D, Park CW, Paik SR, Choi KY. The modification of alpha‐synuclein by dicarbonyl compounds inhibits its fibril‐forming process. Biochim Biophys Acta. 2009; 1794 , 421–30. doi: 10.1016/j.bbapap.2008. - 58.
Padmaraju V, Bhaskar JJ, Prasada RUJ, Salimath PV, Rao KS. Role of advanced glycation on aggregation and DNA binding properties of alpha‐synuclein. J Alzheimers Dis. 2011; 24 , 211–21. doi: 10.1007/s13105‐011‐0091‐5. - 59.
Chen L, Wei Y, Wang X, He R. Ribosylation rapidly induces alpha‐synuclein to form highly cytotoxic molten globules of advanced glycation end products. PLoS One 2010; 5 : e9052. doi: 10.1371/journal.pone.0009052. - 60.
Choi YG, Lim S. N(Varepsilon)‐(carboxymethyl)lysine linkage to alpha‐synuclein and involvement of advanced glycation end products in alpha‐synuclein deposits in an MPTP‐intoxicated mouse model. Biochimie. 2010; 92(10) , 1379–86. doi: 10.1016/ j.biochi.2010.06.025. - 61.
Tagami U, Akashi S, Mizukoshi T, Suzuki E, Hirayama K. Structural studies of the Maillard reaction products of a protein using ion trap mass spectrometry. J Mass Spectrom. 2000; 35 , 131–8. doi: 10.1002/(SICI)1096‐9888(200002)35:2. - 62.
Fazili NA, Naeem A. In vitro hyperglycemic condition facilitated the aggregation of lysozyme via the passage through a molten globule state. Cell Biochem Biophys. 2013; 66 , 265–75. doi: 10.1007/s12013‐012‐9479‐2. - 63.
Ghosh S, Pandey NK, Singha Roy A, Tripathy DR, Dinda AK, Dasgupta S. Prolonged glycation of hen egg white lysozyme generates non amyloidal structures. PLoS One 2013; 8 , e74336. doi: 10.1371/journal.pone.0074336. - 64.
Adrover M, Mariño L, Sanchis P, Pauwels K, Kraan Y, Lebrun P, Vilanova B, Muñoz F, Broersen K, Donoso J. Mechanistic insights in glycation‐induced protein aggregation. Biomacromolecules. 2014; 15(9) , 3449–62. doi: 10.1021/bm501077j. - 65.
Mendez DL, Jensen RA, McElroy LA, Pena JM, Esquerra RM. The effect of non‐enzymatic glycation on the unfolding of human serum albumin. Arch Biochem Biophys. 2005; 444 , 92–99. doi: 10.1016/j.abb.2005.10.019. - 66.
Sattarahmady N, Moosavi‐Movahedi AA, Ahmad F, Hakimelahi GH, Habibi‐Rezaei M, Saboury AA, Sheibani N. Formation of the molten globule‐like state during prolonged glycation of human serum albumin. Biochim Biophys Acta. 2007; 1770 , 933–42. doi: 10.1016/j.bbagen.2007.02.001. - 67.
Rondeau P, Navarra G, Cacciabaudo F, Leone M, Bourdon E, Militello V. Thermal aggregation of glycated bovine serum albumin. Biochim Biophys Acta. 2010; 1804 , 789–98. doi: 10.1016/j.bbapap.2009.12.003. - 68.
Khan MS, Dwivedi S, Priyadarshini M, Tabrez S, Siddiqui MA, Jagirdar H, Al‐Senaidy AM, Al‐Khedhairy AA, Musarrat J. Ribosylation of bovine serum albumin induces ROS accumulation and cell death in cancer line (MCF‐7). Eur Biophys J. 2013; 42 , 811–18. doi: 10.1007/s00249‐013‐0929‐6. - 69.
Szkudlarek A, Sułkowska A, Maciążek‐Jurczyk M, Chudzik M, Równicka‐Zubik J. Effects of non‐enzymatic glycation in human serum albumin. Spectroscopic analysis. Spectrochim Acta A Mol Biomol Spectrosc. 2016; 152 , 645–53. doi: 10.1016/j.saa.2015.01.120. - 70.
Vetter SW, Indurthi VS. Moderate glycation of serum albumin affects folding, stability, and ligand binding. Clin Chim Acta. 2011; 412 , 2105–16. doi: 10.1016/j.cca.2011.07.022. - 71.
Sattarahmady N, Moosavi‐Movahedi AA, Habibi‐Rezaei M, Ahmadian S, Saboury AA, Heli H, Sheibani N. Detergency effects of nanofibrillar amyloid formation on glycation of human serum albumin. Carbohydr Res. 2008; 343 , 2229–34. doi: 10.1016/j.carres.2008.04.036. - 72.
Wei Y, Chen L, Chen J, Ge L, He R Q. Rapid glycation with D‐ribose induces globular amyloid‐like aggregations of BSA with high cytotoxicity to SH‐SY5Y cells. BMC Cell Biol. 2009; 10 , 10. doi: 10.1186/1471‐2121‐10‐10. - 73.
Infusini G, Iannuzzi C, Vilasi S, Maritato R, Birolo L, Pagnozzi D, Pucci P, Irace G, Sirangelo I. W‐F substitutions in apomyoglobin increase the local flexibility of the N‐terminal region causing amyloid aggregation: a H/D exchange study. Protein Pept Lett. 2013; 20(8) , 898–904. - 74.
Vilasi A, Vilasi S, Romano R, Acernese F, Barone F, Balestrieri ML, Maritato R, Irace G, Sirangelo I. Unraveling amyloid toxicity pathway in NIH3T3 cells by a combined proteomic and 1 H‐NMR metabonomic approach. J Cell Physiol. 2013; 228(6) , 1359–67. doi: 10.1002/jcp.24294. - 75.
Sirangelo I, Giovane A, Maritato R, D’Onofrio N, Iannuzzi C, Giordano A, Irace G, Balestrieri ML. Platelet‐activating factor mediates the cytotoxicity induced by W7FW14F apomyoglobin amyloid aggregates in neuroblastoma cells. J Cell Biochem. 2014; 115(12) , 2116–22. doi: 10.1002/jcb.24888. - 76.
Iannuzzi C, Maritato R, Irace G, Sirangelo I. Glycation accelerates fibrillization of the amyloidogenic W7FW14F apomyoglobin. PLoS One. 2013; 8(12) , e80768. doi: 10.1371/journal.pone.0080768. - 77.
Iannuzzi C, Maritato R, Irace G, Sirangelo I. Misfolding and amyloid aggregation of apomyoglobin. Int J Mol Sci. 2013; 14(7) , 14287–300. doi: 10.3390/ijms140714287. - 78.
Iannuzzi C, Irace G, Sirangelo I. Differential effects of glycation on protein aggregation and amyloid formation. Front Mol Biosci. 2014; 1 , 9. doi: 10.3389/fmolb.2014.00009. - 79.
Iannuzzi C, Carafa V, Altucci L, Irace G, Borriello M, Vinciguerra R, Sirangelo I. Glycation of wild‐type apomyoglobin induces formation of highly cytotoxic oligomeric species. J Cell Physiol. 2015; 230(11) , 2807–20. doi:10.1002/jcp.25011. - 80.
Stefani M. Protein aggregation diseases: toxicity of soluble prefibrillar aggregates and their clinical significance. Methods Mol Biol. 2010; 648 , 25–41. doi: 10.1007/978‐1‐60761‐756‐3_2. - 81.
Stefani M. Structural features and cytotoxicity of amyloid oligomers: implications in Alzheimer's disease and other diseases with amyloid deposits. Prog Neurobiol. 2012; 99(3) , 226–45. doi: 10.1016/j.pneurobio.2012.03.002. - 82.
Cecchi C, Stefani M. The amyloid‐cell membrane system. The interplay between the biophysical features of oligomers/fibrils and cell membrane defines amyloid toxicity. Biophys Chem. 2013; 182 , 30–43. doi: 10.1016/j.bpc.2013.06.003. - 83.
Calamai M, Evangelisti E, Cascella R, Parenti N, Cecchi C, Stefani M, Pavone F. Single molecule experiments emphasize GM1 as a key player of the different cytotoxicity of structurally distinct Aβ1‐42 oligomers. Biochim Biophys Acta. 2016; 1858(2) , 386–92. doi: 10.1016/j.bbamem.2015.12.009. - 84.
Salahuddin P, Rabbani G, Khan RH. The role of advanced glycation end products in various types of neurodegenerative disease: a therapeutic approach. Cell Mol Biol Lett. 2014; 19(3) , 407–37. doi: 10.2478/s11658‐014‐0205‐5. - 85.
Münch G, Westcott B, Menini T, Gugliucci A. Advanced glycation endproducts and their pathogenic roles in neurological disorders. Amino Acids. 2012; 42(4) , 1221–36. doi: 10.1007/s00726‐010‐0777‐y. - 86.
Takeuchi M, Yamagishi S. TAGE (toxic AGEs) hypothesis in various chronic diseases. Med Hypotheses. 2004; 63(3) , 449–52. - 87.
Nass N, Bartling B, Navarrete Santos A, Scheubel RJ, Börgermann J, Silber RE, Simm A. Advanced glycation end products, diabetes and ageing. Z Gerontol Geriatr. 2007; 40(5) , 349–56. - 88.
Engelen L, Stehouwer CD, Schalkwijk CG. Current therapeutic interventions in the glycation pathway: evidence from clinical studies. Diabetes Obes Metab. 2013; 15(8) , 677–89. doi: 10.1111/dom.12058. - 89.
Nagai R, Shirakawa J, Ohno R, Moroishi N, Nagai M. Inhibition of AGEs formation by natural products. Amino Acids. 2014; 46(2) , 261–6. doi: 10.1007/s00726‐013‐1487‐z. - 90.
Sadowska‐Bartosz I, Bartosz G. Prevention of protein glycation by natural compounds. Molecules. 2015; 20(2) , 3309–34. doi: 10.3390/molecules20023309.