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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Alzheimers Dis. Author manuscript; available in PMC 2010 April 1.
Published in final edited form as:
PMCID: PMC2765716

Oxidative Stress in Diabetes and Alzheimer’s Disease


Oxidative stress plays a major role in diabetes as well as in Alzheimer’s disease and other related neurological diseases. Intracellular oxidative stress arises due to the imbalance in the production of reactive oxygen/reactive nitrogen species and cellular antioxidant defense mechanisms. In turn, the excess reactive oxygen/reactive nitrogen species mediate the damage of proteins and nucleic acids, which have been shown to have direct and deleterious consequences in diabetes and Alzheimer’s disease. Oxidative stress also contributes to the production of advanced glycation end products through glycoxidation and lipid peroxidation. The advanced glycation end products and lipid peroxidation products are ubiquitous to diabetes and Alzheimer’s disease and serve as markers of disease progression in both disorders. Antioxidants and advanced glycation end products inhibitors, either induced endogenously or exogenously introduced, may counteract with the deleterious effects of the reactive oxygen/reactive nitrogen species and thereby, in prevention or treatment paradigms, attenuate or substantially delay the onset of these devastating pathologies.

Keywords: advanced glycation end products, AGE inhibitors, Alzheimer’s disease, diabetes, glycation, Maillard reaction, oxidative stress, protein crosslinks


Oxidative stress, the direct result of the imbalance between the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and intracellular antioxidant defenses, is invariably involved in the onset of diabetes and neurological pathologies such as Alzheimer’s disease (AD), Parkinson’s disease, and amyotrophic lateral sclerosis [1]. Diabetes, in many cases, usually results in further complications such as cardiovascular disease, atherosclerosis, and diabetic nephropathy. Thus, the hypothesis of diabetes leading, in part, to the onset of AD is an appealing topic and is hotly debated in the current literature.

In addition to oxidative stress[2, 3], cell cycle abnormalities also play a vital role in the pathogenesis of AD[46], as highlighted in the two-hit hypothesis that encompasses both oxidative stressors and mitotic insults for the onset of AD [79]. By analyzing the presence of both oxidative stress responses and abnormalities in mitotic signaling in the same neurons in many cases of AD, it was found that while each stressor can independently initiate cellular dysfunction, both are necessary to propagate disease pathogenesis. Similar hypotheses encompassing multiple sites of action, including genetic and receptors for advanced glycation end products (RAGEs), have also been proposed for the development of diabetes [10]. Interestingly, although AD and diabetes are among the most prevalent diseases in developed countries, a complete cure has, to date, evaded pharmaceutical intervention. At best, disease progression can be delayed or controlled with available treatments. Especially in AD, the causative factors are still not entirely clear. However, both diabetes and AD have common pathogenic factors and evidence suggests oxidative stress as a major factor causing these pathologies[11].

The major species responsible for oxidative stress is the overproduction or ROS and RNS, a major source of which is mitochondrial dysfunction [12]. ROS, which include superoxide radical anion and hydroxyl radicals are involved in the damage of lipids, DNA, and protein modifications. Minor modifications of the nucleic acid bases are repaired through base excision repair involving DNA glycosylase and AP endonuclease, which are located in nuclei and mitochondria. The progression of AD is associated with the diminished expression of these DNA repair enzymes[13, 14]. The accumulation of the oxidatively damaged nucleic acids and proteins likely exceed the limit of cellular repair and detoxification mechanisms and leads to the onset or progression of diabetic and neurological pathologies. In general, accumulation of oxidatively damaged proteins, lipids, and nucleic acids correlate with the onset of age-related diseases, especially in diabetes and AD [15], indicative of one and the same common pathological mechanisms.

Glycoxidation and lipid peroxidation, which are mediated by ROS, generate a variety of reactive carbonyl compounds. These electrophilically-activated carbonyl compounds further react with cellular proteins, lipids, and nucleic acids resulting in protein crosslinking and DNA damage. A variety of advanced glycation and advanced lipid peroxidation products (AGEs and ALEs), some of which are intensely fluorescent, are produced during these slow and complex reactions [16]. AGEs and ALEs, through their interaction with receptors for advanced glycation end products (RAGEs), further activate signal transduction, inducing formation of proinflammatory cytokines such as interleukin-6 (IL-6) [17]. The AGE-RAGE interactions are partially responsible for diabetic neuropathy and nephropathy [18]. RAGEs are multi-ligand receptors, and their interaction with amyloid-β peptides exaggerates neuronal stress and neuroinflammation, resulting in impaired learning [19]. Therefore, blocking RAGEs as well as AGE/ALE-inhibitors may provide an attractive strategy for the treatment of diabetes as well as AD [20].


A variety of ROS and RNS are produced in vivo through both enzymatic and nonenzymatic routes. ROS include superoxide radical anion, hydroxyl radical, alkoxy radicals, and singlet oxygen. The hydroxyl radical is an especially highly reactive species and has a relatively short life time. It is abundantly produced in the mitochondria during respiration cycles and reacts with the proteins, lipids, and nucleic acids in the vicinity of its production. Peroxynitrous acid is one of the major RNS found intracellularly and is involved in the rapid nitration of aromatic residues of proteins, such as tyrosine to give 3-nitrotyrosine, which may alter the protein structure, and is also a marker of oxidative stress [3, 21]. Apolipoprotein E (ApoE)-deficient mice show significantly elevated concentrations of 3-nitrotyrosine, indicating ApoE may modulate the oxidative stress produced by peroxynitrite [22]. Peroxynitrous acid is an additional source of hydroxyl radicals and may in fact be a dominant pathway in diabetes[23].

Transition metal ions, typically Cu(I) and Fe(II), are capable of reducing molecular oxygen to superoxide radical ion via single electron transfer and are involved in the pathogenesis of AD [24, 25]. Other sources of superoxide radical anions are the mitochondrial respiration and NADPH oxidases in AD and diabetes. The superoxide radical anion is a source of hydrogen peroxide through either metal ion reduction followed by protonolysis or via superoxide dismutase. Superoxide radical anion, as well as hydrogen peroxide, is a significantly less reactive species than the hydroxyl radical, which is formed by the transition metal-mediated Fenton reaction of hydrogen peroxide.

Superoxide radical anion forms peroxynitrous acid through its reaction with intracellularly available nitric oxide. Inducible nitric oxide synthase (iNOS) was shown as a significant source of ROS in the streptozotocin-induced diabetic rats [23]. Nitrous acid is also effective in the formation of DNA-protein crosslinks through oxidative modification of guanine residues [2629].


Maillard reaction of reducing sugars (e.g., glucose, ribose, ascorbate) with amino groups of lysine or arginine residues of proteins, followed by Amadori rearrangement, and further ROS-mediated glycoxidations, give a complex product mixture, collectively called AGEs [3033]. AGEs may exist as protein cross-links or as modification of the side chains of a single protein, and significantly alter the protein conformations leading to protein inactivation. Numerous AGEs have been isolated and characterized after cleavage from the protein backbones, by spectroscopic analysis. AGEs involving protein cross-links include pentosidine, a dimer of arginine and lysine; MOLD, a dimer of two lysine residues; and MODIC and GODIC, dimers of arginine and lysine residues. Examples of AGEs resulting from the single protein modification are pyrraline and Nε-(carboxymethyl)lysine (CML), the lysine-residue modified products, and argpyrimidine, an arginine-residue modified protein. Although many other AGEs, including the hydroimidazolone adduct MG-H1, have been characterized in diabetes, this review focuses on those AGEs which have common occurrence in AD and diabetes [34]. It must, however, be pointed out that glycoxidation and oxidative stress are mutually dependent and reinforce each other. Thus, while the sources of oxidative stress may widely differ in diabetes and AD, and while a number of AGEs accumulate in both conditions, other AGEs found in diabetes have yet to be characterized in AD.

Methylglyoxal, an intermediary degradation product of Maillard reactions, is derived from polyol pathways and forms adducts with DNA nucleic acid bases, giving N2-(1-carboxyethyl)-2′-deoxyguanosine as one of the major AGEs [35]. Similarly, methylglyoxal adducts of lysine residues of proteins have been characterized as N2-(carboxyethyl)lysine (CEL) [36, 37]. CEL-modified proteins are detected in the distal tubule epithelial cells in diabetic rats [38].

Pentosidine and CML are shown to be common to both diabetes and AD pathologies and may serve as markers of the disease progression [2, 3944]. The question of whether AGEs are the cause or consequence of the pathology is not clear, although there is likely a primary role of oxidative stress in AD [45]. However, their interactions with RAGEs would lead to deleterious signal transduction resulting in cellular degeneration or apoptosis, or the generation of other inflammatory compounds[4650].

To alleviate the deleterious effects of AGE in diabetes, a variety of AGE inhibitors were developed, whose mechanisms rely on transition metal ion chelating properties, high reactivity with the carbonyl groups, or breaking of the cross-links(vide infra).


Polyunsaturated fatty acids, arachidonic acid, and docasahexaenoic acid are abundant in the cerebral cortex and visual system, and are uniformly distributed in all cell types in brain [51, 52]. ROS-mediated lipid peroxidation of polyunsaturated fatty acids gives rise to several reactive α,β-unsaturated aldehydes, among which 4-hydroxy-trans-2-nonenal (HNE), 4-oxo-trans-2-nonenal (4-ONE), acrolein, and 4-oxo-trans-2-hexenal, all of which are well recognized neurotoxic agents. These compounds are prone to undergo reactions with amino groups of proteins at the carbonyl group to form Schiff bases as well as Michael additions (conjugate additions) on the olefinic moiety adjacent to the carbonyl group, resulting in protein crosslinks and thereby protein inactivation. They also readily undergo Michael reactions with sulfhydryl group of protein cysteines and nucleic acid bases, the latter also resulting in DNA damage through crosslinking [53].

HNE is a widely recognized lipid peroxidation end product and its involvement in neuronal loss in AD is demonstrated[5358]. Although the exact mechanism of the neurotoxicity due to HNE is still in debate, one idea is that its reaction with microtubule protein-cysteine sulfhydryl groups would disrupt microtubule network [53]. 4-ONE is especially significantly more reactive than HNE and is substantially more toxic [59, 60]. HNE and 4-ONE modify the structure of the protein disulfide isomerase, which is critical for maintaining correct disulfide bonds in the protein, by reacting with protein sulfhydryl groups[61]. Glutathione is capable of attenuating the damage caused by HNE and 4-ONE, as the sulfhydryl groups of glutathione effectively compete with those of the proteins. However, glutathione levels are usually depleted in chronic diabetes or AD cases. Similarly, other cellular antioxidant mechanisms, e.g., those involving superoxide dismutase and glyoxalase are also downregulated in cases of AD[62, 63]. Alternatively, increased concentrations of HNE are countered by the cellular expressions of antioxidant heat shock proteins, heme oxygenase-1 (HO-1), and thioredoxin reductase-1 (Trx-R1) in cases of diabetic nephropathy[61] and AD [56, 64, 65]. Low density lipoproteins may act as quenching agents for HNE as it has been shown that as many as 486 molecules of HNE are bound to a single particle of low density lipoprotein[66]. Additionally, lipid peroxidation products may be quenched by neurofilaments [67]and/or microtubules [6870].

Sayre and coworkers have characterized the lysine adducts of HNE and 4-ONE by using mass spectroscopy [71]. The Michael adducts of HNE with lysine, histidine, and cysteine residues of proteins may form cyclic hemiacetals, which can further form Schiff bases by reaction with other histidine (through imidazole nitrogen) or lysine (through ε-amino group) residues of proteins, resulting in intra- or inter-molecular protein crosslinks. The resulting altered protein conformations can lead to enzyme inactivation and induce cellular signal transduction [72]. In the latter, elevated concentrations are correlated with an upregulation of receptor tyrosine kinases and a downregulation of nuclear factor kappa B [72]. Amyloid-β-induced oxidative stress, in part, may be due to HNE and related pro-oxidant molecules, and it has been demonstrated that HNE-mediated activation of mitogen activated protein kinases known to be upregulated in AD [73, 74] is an early event prior the amyloid-β-induced neuronal apoptosis [75]. Mitochondria are also important in the oxidative damage in AD and, perhaps, diabetic complications [7679]. AD-type changes can be induced in control fibroblasts using N-methylprotoporphyrin, which inhibits cytochrome oxidase assembly, an effect attenuated by antioxidants, N-acetlycysteine and lipoic acid [80]. In models of diabetes, controlling increased levels of mitochondrial-derived ROS by normalizing superoxide mitigated glucose-induced formation of AGEs [8183]. A major limitation in the study of oxidative stress in AD is the paucity of cellular models homologous to AD. In this regard, olfactory neurons may be used as a reliable model since cultured olfactory neurons from patients with AD show elevated levels of lipid peroxidation products such as CML and HNE, as well as upregulation of HO-1, strikingly similar to the findings in vulnerable neurons in the brain [84, 85].


Oxidative stress is one of the earliest events in the neurological and pathological changes of AD [45], while the effects of oxidative stress are manifested in the slow accumulation of AGEs and ALEs in diabetes. Oxidative stress leads to the irreversible protein aggregation and consequent neuronal degeneration in AD [8688]. Advanced lipoxidation products, such as HNE, bind to phosphorylated tau protein to form paired helical filaments, accelerating the formation of neurofibrillary tangles. Thus, antioxidant therapy in combination with AGE inhibitor therapy may be effective approaches for AD and diabetes-related complications.

Oxidative stress also results in the covalent crosslinking of tau filaments to form large aggregates that are resistant to proteolytic cleavage. Larbig and coworkers reported a series of inhibitors for the tau protein aggregation [89]. Remarkably, thiazolium-based compounds, which are also AGE inhibitors and potentially useful for diabetic therapy, are effective inhibitors of tau aggregation. 4-(4-bromophenyl)-2-(4-pyridoylhydrazino)-1,3-thiazole shows an IC50 value of 18 μM.

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AGE inhibitors and AGE crosslink breakers

Much of the initial attention towards AGE inhibitors was focused on aminoguanidine, which traps electrophilically activated 1,3-dicarbonyl compounds, the precursors of AGEs[9093]. This compound was not approved by the US Food and Drug Administration due to adverse side effects in diabetic patients during Phase III clinical trials, and the search for safer alternatives continues. Pyridoxamine (Vitamin B6, Pyridorin) and thiamin pyrophosphate are potential alternatives to aminoguanidine, as the former suppresses the formation CML [9496]. Furthermore, these compounds are also good metal ion chelators and attenuate oxidative stress. N-Acetylcysteine and lipoic acid act as inhibitors of ALEs through attenuation of oxidative stress. While the AGE-inhibitory effect of these compounds is not clearly understood, similar mechanism may operate in case of AGEs.

Carnosine, homocarnosine, and related compounds are potentially suitable as AGE inhibitors although further studies are needed to prove their efficacy in diabetes an AD [97]. Carnosine protects superoxide dismutase, catalase, and α-crystallin from nonenzymatic glycation and protein crosslinking [98]. OPB-9195 inhibits AGE formation, especially pentosidine and CML, apparently through carbonyl trapping and metal ion chelation [99, 100]. Thiazolium-based compounds such as Alagebrium chloride (ALT-711) and N-phenyacyl-1,3-thiazolium bromide (PTB) are effective AGE crosslink breakers, and are potentially useful drugs for diabetes and AD [101103]. It should, however, be pointed out that the mechanisms of the action of the latter compounds is not clearly demonstrated. In addition to their action as crosslink breakers of AGEs derived from 1,2-dicarbonyl compounds, they may also act as antioxidants through chelation of transition metal ions. The development of these drugs as therapeutics thus depends on the detailed understanding of their mechanisms of action.

An alternative strategy involves removal of AGEs through the soluble receptors for AGEs (sRAGEs) [104]. Poor glycemic control in diabetes results in decreased concentrations of sRAGES, and upon insulin treatment, significant improvements in the levels of sRAGEs were observed, with concomitant decrease in AGEs [105]. Plasma levels of sRAGEs in healthy humans is in the range of 1500 pg/mL [106]. Treatment of diabetic patients with Rosiglitazone, a 2,4-thiazolidine dione derivative, results in increase of plasma sRAGEs, comparable to controls [107]. Significant amounts of plasma sRAGEs are also produced when angiotensin converting enzyme inhibitors (ACEi; e.g., perindopril) were used for the treatment of diabetes [108]. Therapeutic approaches which attenuate AGEs and insulin resistance are thus better suited for delaying the onset of AD or diabetes related complications. Protective effects of sRAGEs has been questioned recently as they are much higher in experimental animal models than those found in vivo, suggesting they may be only markers of inflammation[109].

Fe(III) and Cu(II) ions are localized in amyloid plaques and neurofibrillary tangles, in cases of AD [24]. Metal ion chelators such as desferrioxamine (Fe(III) chelator), tetrathiomolybdate (Cu(II) chelator), and mercaptopropanol (Pb(II) and Hg(II) chelator) attenuate the expression of the amyloid-β protein precursor, and thereby decrease secretion of the amyloid-β peptide as well as reduce amyloid-β toxicity [110]. As such, desferrioixamine and clioquinol, a Cu(II) chelator, may be potentially useful therapeutic sin AD [111].


Oxidative stress plays a vital role in the pathogenesis of diabetes and AD, as well as related diseases. Oxidative modification of proteins, lipids, and nucleic acids, through glycoxidations and lipid peroxidations generate a complex array of AGEs and ALEs which are increasingly shown to be prevalent in AD, diabetic neuropathy, and diabetic nephropathy. AGEs, through reaction with RAGEs, further generate inflammatory cytokines and induce signal transduction which may result in cell apoptosis. Specifically, to counter the effects of oxidative stress in these pathologies, therapeutic strategies involving AGE inhibitors and anti-inflammatory antioxidants appear to be most promising. By comparing the stressors and responses that are common between the two conditions, understanding the mechanisms and possible therapeutic avenues may provide alternate treatment modalities for both diabetes and AD.

Scheme 1
Cellular generation of ROS and RNS. Superoxide radical anions generated from the transition metal ion mediated reduction of molecular oxygen is transformed into hydrogen peroxide either through superoxide dismutase catalyzed reaction or by further reduction ...
Scheme 2
Structures of representative AGEs. AGEs are the end products of complex series of glycoxidation reactions involving proteins and reducing sugars. Some of the AGEs are protein crosslinks (e.g., pentosidine, MOLD, GOLD, MODIC, GODIC), while others are single ...
Scheme 3
Lipid peroxidation. Polyunsaturated fatty acids undergo oxidative degrations mediaited by ROS and RNS. A variety of deleterious and neurotoxic γ-hydroxy and γ-keto aldehydes, such as HNE, 4-ONE, and acrolein are formed through lipid peroxidation. ...
Scheme 4
Reactions of HNE and 4-ONE. HNE and 4-ONE are highly reactive with ε-amino grop of lysine, imidazole nitrogen of the histidine, and sulfhydryl groups of cysteine moities. 4-ONE is much more reactive than HNE and substantially neurotoxic. HNE and ...
Scheme 5
Structures of and AGE-inhibitors. There is an active interest in the development of AGE inhibitors that show therapeutic promise in diabetes, and AD. AGE inhibitors may have varied mechanisms of their action, which involve carbonyl trapping, metal ion ...
Scheme 6
Structures of metal ion chelators. Clioquinol and desferrioxamine are chelators of transition metal ions, Cu(II) and Fe(III), respectively. Particularly, in AD, the metal ion concentration is elevated at the sites of amyloid-β and neurofibrillary ...


Work in the author’s laboratories is supported by the NIH and the Alzheimer’s Association.


Dr. Smith is, or has in the past been, a paid consultant for, owns equity or stock options in and/or receives grant funding from Canopus BioPharma, Medivation, Neurotez, Neuropharm, Panacea Pharmaceuticals, and Voyager Pharmaceuticals. Dr. Perry is a paid consultant for and/or owns equity or stock options in Takeda Pharmaceuticals, Voyager Pharmaceuticals, Panacea Pharmaceuticals and Neurotez Pharmaceuticals.


1. Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G. Oxidative damage is the earliest change of Alzheimer disease: therapeutic opportunities. In: Sun M-K, editor. Research Progress in Alzheimer’s Disease and Dementia. Nova Science Publishers, Inc; New York: 2007. pp. 301–317.
2. Smith MA, Sayre LM, Monnier VM, Perry G. Radical AGEing in Alzheimer’s disease. Trends Neurosci. 1995;18:172–176. [PubMed]
3. Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G. Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci. 1997;17:2653–2657. [PubMed]
4. McShea A, Harris PL, Webster KR, Wahl AF, Smith MA. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer’s disease. Am J Pathol. 1997;150:1933–1939. [PubMed]
5. Ogawa O, Zhu X, Lee HG, Raina A, Obrenovich ME, Bowser R, Ghanbari HA, Castellani RJ, Perry G, Smith MA. Ectopic localization of phosphorylated histone H3 in Alzheimer’s disease: a mitotic catastrophe? Acta Neuropathol (Berl) 2003;105:524–528. [PubMed]
6. Harris PL, Zhu X, Pamies C, Rottkamp CA, Ghanbari HA, McShea A, Feng Y, Ferris DK, Smith MA. Neuronal polo-like kinase in Alzheimer disease indicates cell cycle changes. Neurobiol Aging. 2000;21:837–841. [PubMed]
7. Zhu X, Lee HG, Perry G, Smith MA. Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta. 2007;1772:494–502. [PubMed]
8. Zhu X, Raina AK, Perry G, Smith MA. Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol. 2004;3:219–226. [PubMed]
9. Zhu X, Perry G, Smith MA. Two hits and you’re out? A novel mechanistic hypothesis of Alzheimer disease. In: Fisher A, Memo M, Stocchi F, Hanin I, editors. Advances in Behavioral Biology, Volume 57, Advances in Alzheimer’s and Parkinson’s Disease: Insights, Progress and Perspectives. Springer Science + Business Media, LLC; New York: 2008. pp. 191–204.
10. Schmidt AM, Stern D. Atherosclerosis and diabetes: the RAGE connection. Curr Atheroscler Rep. 2000;2:430–436. [PubMed]
11. Smith MA, Sayre LM, Perry G. Diabetes mellitus and Alzheimer’s disease: glycation as a biochemical link. Diabetologia. 1996;39:247. [PubMed]
12. Zhu X, Su B, Wang X, Smith MA, Perry G. Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci. 2007;64:2202–2210. [PubMed]
13. Nakabeppu Y, Tsuchimoto D, Ichinoe A, Ohno M, Ide Y, Hirano S, Yoshimura D, Tominaga Y, Furuichi M, Sakumi K. Biological significance of the defense mechanisms against oxidative damage in nucleic acids caused by reactive oxygen species: from mitochondria to nuclei. Ann N Y Acad Sci. 2004;1011:101–111. [PubMed]
14. Reddy VP, Beyaz A, Perry G, Cooke MS, Sayre LM, Smith MA. The role of oxidative damage to nucleic acids in the pathogenesis of neurological disease. In: Evans MD, Cooke MS, editors. Oxidative Damage to Nucleic Acids. Landes Bioscience and Springer Science+Business Media, LLC; Austin: 2007. pp. 123–140.
15. Stadtman ER. Protein oxidation in aging and age-related diseases. Ann N Y Acad Sci. 2001;928:22–38. [PubMed]
16. Sayre LM, Lin D, Yuan Q, Zhu X, Tang X. Protein adducts generated from products of lipid oxidation: focus on HNE and one. Drug Metab Rev. 2006;38:651–675. [PubMed]
17. Yan SF, Barile GR, D’Agati V, Du Yan S, Ramasamy R, Schmidt AM. The biology of RAGE and its ligands: uncovering mechanisms at the heart of diabetes and its complications. Curr Diab Rep. 2007;7:146–153. [PubMed]
18. Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med. 2005;83:876–886. [PubMed]
19. Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF, Yan SD. RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer’s disease. Curr Mol Med. 2007;7:735–742. [PubMed]
20. Mecocci P, Mariani E, Polidori MC, Hensley K, Butterfield DA. Antioxidant agents in Alzheimer’s disease. Cent Nerv Syst Agents Med Chem. 2008;8:48–63.
21. Leeuwenburgh C, Hansen P, Shaish A, Holloszy JO, Heinecke JW. Markers of protein oxidation by hydroxyl radical and reactive nitrogen species in tissues of aging rats. Am J Physiol. 1998;274:R453–461. [PubMed]
22. Matthews RT, Beal MF. Increased 3-nitrotyrosine in brains of Apo E-deficient mice. Brain Res. 1996;718:181–184. [PubMed]
23. Stadler K, Bonini MG, Dallas S, Jiang J, Radi R, Mason RP, Kadiiska MB. Involvement of inducible nitric oxide synthase in hydroxyl radical-mediated lipid peroxidation in streptozotocin-induced diabetes. Free Radic Biol Med. 2008 in press. [PMC free article] [PubMed]
24. Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A. 1997;94:9866–9868. [PubMed]
25. Sayre LM, Perry G, Harris PL, Liu Y, Schubert KA, Smith MA. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition metals. J Neurochem. 2000;74:270–279. [PubMed]
26. Caulfield JL, Wishnok JS, Tannenbaum SR. Nitric oxide-induced interstrand cross-links in DNA. Chem Res Toxicol. 2003;16:571–574. [PubMed]
27. Chen HJ, Chiu WL, Lin WP, Yang SS. Investigation of DNA-protein cross-link formation between lysozyme and oxanine by mass spectrometry. Chembiochem. 2008;9:1074–1081. [PubMed]
28. Chen HJ, Hsieh CJ, Shen LC, Chang CM. Characterization of DNA--protein cross-links induced by oxanine: cellular damage derived from nitric oxide and nitrous acid. Biochemistry (Mosc) 2007;46:3952–3965. [PubMed]
29. Edfeldt NB, Harwood EA, Sigurdsson ST, Hopkins PB, Reid BR. Solution structure of a nitrous acid induced DNA interstrand cross-link. Nucleic Acids Res. 2004;32:2785–2794. [PMC free article] [PubMed]
30. Reddy VP, Obrenovich ME, Atwood CS, Perry G, Smith MA. Involvement of Maillard reactions in Alzheimer disease. Neurotox Res. 2002;4:191–209. [PubMed]
31. Ulrich P, Cerami A. Protein glycation, diabetes, and aging. Recent Prog Horm Res. 2001;56:1–21. [PubMed]
32. Spiteller G. Peroxyl radicals are essential reagents in the oxidation steps of the Maillard reaction leading to generation of advanced glycation end products. Ann N Y Acad Sci. 2008;1126:128–133. [PubMed]
33. Reddy VP, Beyaz A. Inhibitors of the Maillard reaction and AGE breakers as therapeutics for multiple diseases. Drug Discov Today. 2006;11:646–654. [PubMed]
34. Rabbani N, Thornalley PJ. The dicarbonyl proteome: proteins susceptible to dicarbonyl glycation at functional sites in health, aging, and disease. Ann N Y Acad Sci. 2008;1126:124–127. [PubMed]
35. Synold T, Xi B, Wuenschell GE, Tamae D, Figarola JL, Rahbar S, Termini J. Advanced glycation end products of DNA: Quantification of N2-(1-carboxyethyl)-2′-deoxyguanosine in biological samples by liquid chromatography electrospray ionization tandem mass spectrometry. Chem Res Toxicol. 2008 in press. [PMC free article] [PubMed]
36. Sell DR, Strauch CM, Shen W, Monnier VM. Aging, diabetes, and renal failure catalyze the oxidation of lysyl residues to 2-aminoadipic acid in human skin collagen: evidence for metal-catalyzed oxidation mediated by alpha-dicarbonyls. Ann N Y Acad Sci. 2008;1126:205–209. [PubMed]
37. Seidel W, Pischetsrieder M. DNA-glycation leads to depurination by the loss of N2-carboxyethylguanine in vitro. Cell Mol Biol (Noisy-le-grand) 1998;44:1165–1170. [PubMed]
38. Nagai R, Fujiwara Y, Mera K, Yamagata K, Sakashita N, Takeya M. Immunochemical detection of Nepsilon-(carboxyethyl)lysine using a specific antibody. J Immunol Methods. 2008;332:112–120. [PubMed]
39. 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 U S A. 1994;91:5710–5714. [PubMed]
40. Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, Scott CW, Caputo C, Frappier T, Smith MA. Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci U S A. 1994;91:7787–7791. [PubMed]
41. Castellani RJ, Harris PL, Sayre LM, Fujii J, Taniguchi N, Vitek MP, Founds H, Atwood CS, Perry G, Smith MA. Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med. 2001;31:175–180. [PubMed]
42. Takeda A, Yasuda T, Miyata T, Goto Y, Wakai M, Watanabe M, Yasuda Y, Horie K, Inagaki T, Doyu M, Maeda K, Sobue G. Advanced glycation end products co-localized with astrocytes and microglial cells in Alzheimer’s disease brain. Acta Neuropathol. 1998;95:555–558. [PubMed]
43. Takeuchi M, Makita Z. Alternative routes for the formation of immunochemically distinct advanced glycation end-products in vivo. Curr Mol Med. 2001;1:305–315. [PubMed]
44. Ahmed N, Argirov OK, Minhas HS, Cordeiro CA, Thornalley PJ. Assay of advanced glycation endproducts (AGEs): surveying AGEs by chromatographic assay with derivatization by 6-aminoquinolyl-N-hydroxysuccinimidyl-carbamate and application to Nepsilon-carboxymethyl-lysine- and Nepsilon-(1-carboxyethyl)lysine-modified albumin. Biochem J. 2002;364:1–14. [PubMed]
45. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001;60:759–767. [PubMed]
46. Maczurek A, Shanmugam K, Munch G. Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer’s disease. Ann N Y Acad Sci. 2008;1126:147–151. [PubMed]
47. Ramasamy R, Yan SF, Herold K, Clynes R, Schmidt AM. Receptor for advanced glycation end products: fundamental roles in the inflammatory response: winding the way to the pathogenesis of endothelial dysfunction and atherosclerosis. Ann N Y Acad Sci. 2008;1126:7–13. [PMC free article] [PubMed]
48. Yan SF, Ramasamy R, Schmidt AM. Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat Clin Pract Endocrinol Metab. 2008;4:285–293. [PubMed]
49. Buetler TM, Leclerc E, Baumeyer A, Latado H, Newell J, Adolfsson O, Parisod V, Richoz J, Maurer S, Foata F, Piguet D, Junod S, Heizmann CW, Delatour T. N(epsilon)-carboxymethyllysine-modified proteins are unable to bind to RAGE and activate an inflammatory response. Mol Nutr Food Res. 2008;52:370–378. [PubMed]
50. Yamagishi S, Nakamura K, Matsui T, Noda Y, Imaizumi T. Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication. Curr Pharm Des. 2008;14:487–495. [PubMed]
51. Diau GY, Hsieh AT, Sarkadi-Nagy EA, Wijendran V, Nathanielsz PW, Brenna JT. The influence of long chain polyunsaturate supplementation on docosahexaenoic acid and arachidonic acid in baboon neonate central nervous system. BMC Med. 2005;3:11. [PMC free article] [PubMed]
52. Montine TJ, Milatovic D, Gupta RC, Valyi-Nagy T, Morrow JD, Breyer RM. Neuronal oxidative damage from activated innate immunity is EP2 receptor-dependent. J Neurochem. 2002;83:463–470. [PubMed]
53. Neely MD, Boutte A, Milatovic D, Montine TJ. Mechanisms of 4-hydroxynonenal-induced neuronal microtubule dysfunction. Brain Res. 2005;1037:90–98. [PubMed]
54. Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, Smith MA. 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem. 1997;68:2092–2097. [PubMed]
55. Liu Q, Raina AK, Smith MA, Sayre LM, Perry G. Hydroxynonenal, toxic carbonyls, and Alzheimer disease. Mol Aspects Med. 2003;24:305–313. [PubMed]
56. Takeda A, Smith MA, Avila J, Nunomura A, Siedlak SL, Zhu X, Perry G, Sayre LM. In Alzheimer’s disease, heme oxygenase is coincident with Alz50, an epitope of tau induced by 4-hydroxy-2-nonenal modification. J Neurochem. 2000;75:1234–1241. [PubMed]
57. Long EK, Murphy TC, Leiphon LJ, Watt J, Morrow JD, Milne GL, Howard JR, Picklo MJ., Sr Trans-4-hydroxy-2-hexenal is a neurotoxic product of docosahexaenoic (22:6; n-3) acid oxidation. J Neurochem. 2008;105:714–724. [PubMed]
58. Stewart BJ, Doorn JA, Petersen DR. Residue-specific adduction of tubulin by 4-hydroxynonenal and 4-oxononenal causes cross-linking and inhibits polymerization. Chem Res Toxicol. 2007;20:1111–1119. [PubMed]
59. Lin D, Lee HG, Liu Q, Perry G, Smith MA, Sayre LM. 4-Oxo-2-nonenal is both more neurotoxic and more protein reactive than 4-hydroxy-2-nonenal. Chem Res Toxicol. 2005;18:1219–1231. [PubMed]
60. Carbone DL, Doorn JA, Kiebler Z, Petersen DR. Cysteine modification by lipid peroxidation products inhibits protein disulfide isomerase. Chem Res Toxicol. 2005;18:1324–1331. [PubMed]
61. Calabrese V, Mancuso C, Sapienza M, Puleo E, Calafato S, Cornelius C, Finocchiaro M, Mangiameli A, Di Mauro M, Stella AM, Castellino P. Oxidative stress and cellular stress response in diabetic nephropathy. Cell Stress Chaperones. 2007;12:299–306. [PMC free article] [PubMed]
62. Casado A, Encarnacion Lopez-Fernandez M, Concepcion Casado M, de La Torre R. Lipid peroxidation and antioxidant enzyme activities in vascular and Alzheimer dementias. Neurochem Res. 2008;33:450–458. [PubMed]
63. Kuhla B, Boeck K, Luth HJ, Schmidt A, Weigle B, Schmitz M, Ogunlade V, Munch G, Arendt T. Age-dependent changes of glyoxalase I expression in human brain. Neurobiol Aging. 2006;27:815–822. [PubMed]
64. Smith MA, Kutty RK, Richey PL, Yan SD, Stern D, Chader GJ, Wiggert B, Petersen RB, Perry G. Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer’s disease. Am J Pathol. 1994;145:42–47. [PubMed]
65. Premkumar DR, Smith MA, Richey PL, Petersen RB, Castellani R, Kutty RK, Wiggert B, Perry G, Kalaria RN. Induction of heme oxygenase-1 mRNA and protein in neocortex and cerebral vessels in Alzheimer’s disease. J Neurochem. 1995;65:1399–1402. [PubMed]
66. Annangudi SP, Deng Y, Gu X, Zhang W, Crabb JW, Salomon RG. Low-density lipoprotein has an enormous capacity to bind (E)-4-hydroxynon-2-enal (HNE): detection and characterization of lysyl and histidyl adducts containing multiple molecules of HNE. Chem Res Toxicol. 2008;21:1384–1395. [PMC free article] [PubMed]
67. Wataya T, Nunomura A, Smith MA, Siedlak SL, Harris PL, Shimohama S, Szweda LI, Kaminski MA, Avila J, Price DL, Cleveland DW, Sayre LM, Perry G. High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. J Biol Chem. 2002;277:4644–4648. [PubMed]
68. Liu Q, Smith MA, Avila J, DeBernardis J, Kansal M, Takeda A, Zhu X, Nunomura A, Honda K, Moreira PI, Oliveira CR, Santos MS, Shimohama S, Aliev G, de la Torre J, Ghanbari HA, Siedlak SL, Harris PL, Sayre LM, Perry G. Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations. Free Radic Biol Med. 2005;38:746–754. [PubMed]
69. Gomez-Ramos A, Diaz-Nido J, Smith MA, Perry G, Avila J. Effect of the lipid peroxidation product acrolein on tau phosphorylation in neural cells. J Neurosci Res. 2003;71:863–870. [PubMed]
70. Santa-Maria I, Smith MA, Perry G, Hernandez F, Avila J, Moreno FJ. Effect of quinones on microtubule polymerization: a link between oxidative stress and cytoskeletal alterations in Alzheimer’s disease. Biochim Biophys Acta. 2005;1740:472–480. [PubMed]
71. Liu Z, Minkler PE, Sayre LM. Mass spectroscopic characterization of protein modification by 4-hydroxy-2-(E)-nonenal and 4-oxo-2-(E)-nonenal. Chem Res Toxicol. 2003;16:901–911. [PubMed]
72. Leonarduzzi G, Robbesyn F, Poli G. Signaling kinases modulated by 4-hydroxynonenal. Free Radic Biol Med. 2004;37:1694–1702. [PubMed]
73. Zhu X, Lee HG, Raina AK, Perry G, Smith MA. The role of mitogen-activated protein kinase pathways in Alzheimer’s disease. Neurosignals. 2002;11:270–281. [PubMed]
74. Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA. Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech Ageing Dev. 2001;123:39–46. [PubMed]
75. Tamagno E, Robino G, Obbili A, Bardini P, Aragno M, Parola M, Danni O. H2O2 and 4-hydroxynonenal mediate amyloid beta-induced neuronal apoptosis by activating JNKs and p38 MAPK. Exp Neurol. 2003;180:144–155. [PubMed]
76. Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med. 2008;14:45–53. [PMC free article] [PubMed]
77. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA. Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci. 2001;21:3017–3023. [PubMed]
78. Swerdlow RH, Khan SM. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses. 2004;63:8–20. [PubMed]
79. Onyango I, Khan S, Miller B, Swerdlow R, Trimmer P, Bennett P., Jr Mitochondrial genomic contribution to mitochondrial dysfunction in Alzheimer’s disease. J Alzheimers Dis. 2006;9:183–193. [PubMed]
80. Moreira PI, Harris PL, Zhu X, Santos MS, Oliveira CR, Smith MA, Perry G. Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts. J Alzheimers Dis. 2007;12:195–206. [PubMed]
81. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615–1625. [PubMed]
82. Takuma K, Yao J, Huang J, Xu H, Chen X, Luddy J, Trillat AC, Stern DM, Arancio O, Yan SS. ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J. 2005;19:597–598. [PubMed]
83. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787–790. [PubMed]
84. Ghanbari HA, Ghanbari K, Harris PL, Jones PK, Kubat Z, Castellani RJ, Wolozin BL, Smith MA, Perry G. Oxidative damage in cultured human olfactory neurons from Alzheimer’s disease patients. Aging Cell. 2004;3:41–44. [PubMed]
85. Perry G, Castellani RJ, Smith MA, Harris PL, Kubat Z, Ghanbari K, Jones PK, Cordone G, Tabaton M, Wolozin B, Ghanbari H. Oxidative damage in the olfactory system in Alzheimer’s disease. Acta Neuropathol (Berl) 2003;106:552–556. [PubMed]
86. Smith MA, Siedlak SL, Richey PL, Nagaraj RH, Elhammer A, Perry G. Quantitative solubilization and analysis of insoluble paired helical filaments from Alzheimer disease. Brain Res. 1996;717:99–108. [PubMed]
87. Liu Q, Xie F, Rolston R, Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G. Prevention and treatment of Alzheimer disease and aging: antioxidants. Mini Rev Med Chem. 2007;7:171–180. [PubMed]
88. Dimakopoulos AC. Protein aggregation in Alzheimer’s disease and other neoropathological disorders. Curr Alzheimer Res. 2005;2:19–28. [PubMed]
89. Larbig G, Pickhardt M, Lloyd DG, Schmidt B, Mandelkow E. Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: a ligand based approach results in successful scaffold hopping. Curr Alzheimer Res. 2007;4:315–323. [PubMed]
90. Webster J, Urban C, Berbaum K, Loske C, Alpar A, Gartner U, de Arriba SG, Arendt T, Munch G. The carbonyl scavengers aminoguanidine and tenilsetam protect against the neurotoxic effects of methylglyoxal. Neurotox Res. 2005;7:95–101. [PubMed]
91. Booth AA, Khalifah RG, Hudson BG. Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation end-products: comparison with aminoguanidine. Biochem Biophys Res Commun. 1996;220:113–119. [PubMed]
92. Rahbar S, Yerneni KK, Scott S, Gonzales N, Lalezari I. Novel inhibitors of advanced glycation endproducts (part II) Mol Cell Biol Res Commun. 2000;3:360–366. [PubMed]
93. Thomas MC, Baynes JW, Thorpe SR, Cooper ME. The role of AGEs and AGE inhibitors in diabetic cardiovascular disease. Curr Drug Targets. 2005;6:453–474. [PubMed]
94. Adrover M, Vilanova B, Frau J, Munoz F, Donoso J. The pyridoxamine action on Amadori compounds: A reexamination of its scavenging capacity and chelating effect. Bioorg Med Chem. 2008;16:5557–5569. [PubMed]
95. Nakamura S, Li H, Adijiang A, Pischetsrieder M, Niwa T. Pyridoxal phosphate prevents progression of diabetic nephropathy. Nephrol Dial Transplant. 2007;22:2165–2174. [PubMed]
96. Ahmed N, Thornalley PJ. Advanced glycation endproducts: what is their relevance to diabetic complications? Diabetes Obes Metab. 2007;9:233–245. [PubMed]
97. Reddy VP, Garrett MR, Perry G, Smith MA. Carnosine: a versatile antioxidant and antiglycating agent. Sci Aging Knowledge Environ 2005. 2005:pe12. [PubMed]
98. Hipkiss AR. Could carnosine or related structures suppress Alzheimer’s disease? J Alzheimers Dis. 2007;11:229–240. [PubMed]
99. Bruno S, Cattaneo D, Perico N, Remuzzi G. Emerging drugs for diabetic nephropathy. Expert Opin Emerg Drugs. 2005;10:747–771. [PubMed]
100. Wada R, Nishizawa Y, Yagihashi N, Takeuchi M, Ishikawa Y, Yasumura K, Nakano M, Yagihashi S. Effects of OPB-9195, anti-glycation agent, on experimental diabetic neuropathy. Eur J Clin Invest. 2001;31:513–520. [PubMed]
101. Susic D. Cross-link breakers as a new therapeutic approach to cardiovascular disease. Biochem Soc Trans. 2007;35:853–856. [PubMed]
102. Bhatwadekar A, Stitt AW. AGE and RAGE inhibitors in the treatment of diabetic retinopathy. Expert Rev Ophthalmol. 2007;2:105–120.
103. Peppa M, Brem H, Cai W, Zhang JG, Basgen J, Li Z, Vlassara H, Uribarri J. Prevention and reversal of diabetic nephropathy in db/db mice treated with alagebrium (ALT-711) Am J Nephrol. 2006;26:430–436. [PubMed]
104. Vasdev S, Gill V, Singal P. Role of advanced glycation end products in hypertension and atherosclerosis: therapeutic implications. Cell Biochem Biophys. 2007;49:48–63. [PubMed]
105. Devangelio E, Santilli F, Formoso G, Ferroni P, Bucciarelli L, Michetti N, Clissa C, Ciabattoni G, Consoli A, Davi G. Soluble RAGE in type 2 diabetes: association with oxidative stress. Free Radic Biol Med. 2007;43:511–518. [PubMed]
106. Prasad K. Soluble receptor for advanced glycation end products (sRAGE) and cardiovascular disease. Int J Angiol. 2006;15:57–68.
107. Tan KC, Chow WS, Tso AW, Xu A, Tse HF, Hoo RL, Betteridge DJ, Lam KS. Thiazolidinedione increases serum soluble receptor for advanced glycation end-products in type 2 diabetes. Diabetologia. 2007;50:1819–1825. [PubMed]
108. Tan KC, Shiu SW, Chow WS, Leng L, Bucala R, Betteridge DJ. Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes. Diabetologia. 2006;49:2756–2762. [PubMed]
109. Humpert PM, Papadopoulos G, Schaefer K, Djuric Z, Konrade I, Morcos M, Nawroth PP, Bierhaus A. sRAGE and esRAGE are not associated with peripheral or autonomic neuropathy in type 2 diabetes. Horm Metab Res. 2007;39:899–902. [PubMed]
110. Rottkamp CA, Raina AK, Zhu X, Gaier E, Bush AI, Atwood CS, Chevion M, Perry G, Smith MA. Redox-active iron mediates amyloid-beta toxicity. Free Radic Biol Med. 2001;30:447–450. [PubMed]
111. Moreira PI, Zhu X, Smith MA, Perry G, Nunomura A. Antioxidant therapies in the prevention and treatment of Alzheimer disease. In: Luo Y, Packer L, editors. Oxidative Stress and Age-Related Neurodegeneration. Taylor & Francis Group; Boca Raton: 2006. pp. 131–145.