Skip to main content

Advertisement

SpringerLink
Log in

Oxidative Stress in Alzheimer’s Disease: Should We Keep Trying Antioxidant Therapies?

  • Review Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The risk of chronic diseases such as Alzheimer’s disease is growing as a result of the continuous increasing average life span of the world population, a syndrome characterized by the presence of intraneural neurofibrillary tangles and senile plaques composed mainly by beta-amyloid protein, changes that may cause a number of progressive disorders in the elderly, causing, in its most advanced stage, difficulty in performing normal daily activities, among other manifestations. Therefore, it is important to understand the underlying pathogenic mechanisms of this syndrome. Nevertheless, despite intensive effort to access the physiopathological pathways of the disease, it remains poorly understood. In that context, some hypotheses have arisen, including the recent oxidative stress hypothesis, theory supported by the involvement of oxidative stress in aging, and the vulnerability of neurons to oxidative attack. In the present revision, oxidative changes and redox mechanisms in Alzheimer’s disease will be further stressed, as well as the grounds for antioxidant supplementation as adjuvant therapy for the disease will be addressed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

AD:

Alzheimer’s disease

AGE:

Advanced glycation end products

ApoE:

Apolipoprotein E

ATPase:

Adenylpyrophosphatase

βA:

Beta-amyloid

BACE-1:

Aspartate β-secretase 1

βAPP:

Protein precursor of βA

CNS:

Central nervous system

DHEAS:

Reduced dehydroepiandrosterone sulfate

GSH-Px:

Glutathione peroxidase

GSK-3β:

Glycogen synthase kinase 3β

H2O2 :

Hydrogen peroxide

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

MDA:

Malondialdehyde

NAC:

N-Acetylcysteine

NFkB:

Nuclear factor kappa B

NMDA:

N-Methyl-d-aspartate

NO:

Nitric oxide

\({\text{O}}_{2}^{ \bullet - }\) :

Superoxide

\({\text{OH}}^{ \bullet }\) :

Hydroxyl radical

ONOO− :

Peroxynitrite radical

PI3K:

Phosphatidylinositol 3-kinase

PS:

Presenilin

RAGE:

AGE receptors

ROS:

Reactive oxygen species

sAPPβ:

Fragment of the amyloid precursor protein

SOD:

Superoxide dismutase

TNF-α:

Tumor necrosis factor alpha

References

  • Adlard PA, Bush AI (2006) Metals and Alzheimer’s disease. J Alzheimers Dis 10:145–163

    PubMed  Google Scholar 

  • Ahmed HH (2012) Modulatory effects of vitamin E, acetyl-l-carnitine and α-lipoic acid on new potential biomarkers for Alzheimer’s disease in rat model. Exp Toxicol Pathol 64:549–556

    CAS  PubMed  Google Scholar 

  • Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF et al (2008) Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 300:1774–1783

    CAS  PubMed Central  PubMed  Google Scholar 

  • Akama KT, Van Eldik LJ (2000) β-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1b- and tumor necrosis factor-α (TNFα)-dependent, and involves a TNFα receptor-associated factor- and NFkB-inducing kinase-dependent signaling mechanism. J Biol Chem 275:7918–7924

    CAS  PubMed  Google Scholar 

  • Akama KT, Albanese C, Pestell RG, Van Eldik LJ (1998) Amyloid-β peptide stimulates nitric oxide production in astrocytes through an NFkB-dependent mechanism. Proc Natl Acad Sci 95:5795–5800

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ali FE, Separovic F, Barrow CJ, Cherny RA, Fraser F, Bush AI et al (2005) Methionine regulates copper/hydrogen peroxide oxidation products of A beta. J Pept Sci 11:353–360

    CAS  PubMed  Google Scholar 

  • Ali FE, Leung A, Cherny RA, Mavros C, Barnham KJ, Separovic F et al (2006) Dimerisation of N-acetyl-l-tyrosine ethyl ester and Abeta peptides via formation of dityrosine. Free Radic Res 40:1–9

    CAS  PubMed  Google Scholar 

  • Alzheimer A (1907) Über Eine Eigenartige Erkankung Der Hirnrinde. Allgemeine Z Psychiatrie Psychisch-Gerichtlichen Medizin 64:146–148

    Google Scholar 

  • Alzheimer’s Disease International (2009) World Alzheimer Report 2009. London

  • Ancelin ML, Christen Y, Ritchie K (2007) Is antioxidant therapy a viable alternative for mild cognitive impairment? Examination of the evidence. Dement Geriatr Cogn Disord 24:1–19

    CAS  PubMed  Google Scholar 

  • Arlt S, Muller-Thomsen T, Beisiegel U, Kontush A (2012) Effect of one-year vitamin C- and E-supplementation on cerebrospinal fluid oxidation parameters and clinical course in Alzheimer’s disease. Neurochem Res 37(12):2706–2714

    CAS  PubMed  Google Scholar 

  • Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM et al (1998) Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem 273:12817–12826

    CAS  PubMed  Google Scholar 

  • Auld DS, Kornecook TJ, Bastianetto S, Quirion R (2002) Alzheimer’s disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition and treatment strategies. Prog Neurobiol 68:209–245

    CAS  PubMed  Google Scholar 

  • Bagi Z, Csekó C, Tóth E, Koller A (2003) Oxidative stress-induced dysregulation of arteriolar wall shear stress and blood pressure in hyperhomocysteinemia is prevented by chronic vitamin C treatment. Am J Physiol 285:H2277–H2283

    CAS  Google Scholar 

  • Barnham KJ, Haeffner F, Ciccotosto GD, Curtain CC, Tew D, Mavros C et al (2004) Tyrosine gated electron transfer is key to the toxic mechanism of Alzheimer’s disease β-amyloid. FASEB J 18:1427–1429

    CAS  PubMed  Google Scholar 

  • Bartosz G (2009) Reactive oxygen species: destroyers or messengers? J Biochem Pharmacol 77:1303–1315

    CAS  Google Scholar 

  • Bartus RT, Emerich DF (1999) Cholinergic markers in Alzheimer disease. JAMA 282(23):2208–2209

    CAS  PubMed  Google Scholar 

  • Batsch NL, Mittelman MS (2012) Overcoming the stigma of dementia. In: Alzheimer’s Disease International, World Alzheimer Report 2012, London

  • Baum L, Lam CWK, Cheung SKK, Kwok T, Lui V, Tsoh J et al (2008) Six-month randomized, placebo controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol 28(1):110–113

    PubMed  Google Scholar 

  • Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38:357–366

    CAS  PubMed  Google Scholar 

  • Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite-the good, the bad, and the ugly. Am J Physiol 40:C1424–C1437

    Google Scholar 

  • Behl C (1999) Alzheimer’s disease and oxidative stress: implications for novel therapeutic approaches. Prog Neurobiol 57:301–323

    CAS  PubMed  Google Scholar 

  • Behl C, Moosmann B (2002) Antioxidant neuroprotection in Alzheimer’s disease as preventive and therapeutic approach. Free Radic Biol Med 33:182–191

    CAS  PubMed  Google Scholar 

  • Behl C, Sagara YR (1997) Mechanism of amyloid beta protein induced neuronal cell death: current concepts and future perspective. J Neural Trasnm Suppl 49:125–134

    CAS  Google Scholar 

  • Behl C, Davis J, Cole GM, Schubert D (1992) Vitamin E protects nerve cells from amyloid β-protein toxicity. Biochem Biophys Res Commun 186:944–952

    CAS  PubMed  Google Scholar 

  • Behl C, Davis JB, Lesley R, Schubert D (1994) Hydrogen peroxide mediates amyloid β-protein toxicity. Cell 77:817–822

    CAS  PubMed  Google Scholar 

  • Bierhaus A, Hofman MA, Ziegler R, Nauroth PP (1998) AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res 37:586–600

    CAS  PubMed  Google Scholar 

  • Bigl K, Gaunitz F, Schmitt A, Rothemund S, Schliebs R, Münch G et al (2008) Cytotoxicity of advanced glycation endproducts in human micro- and astroglial cell lines depends on the degree of protein glycation. J Neural Transm 115:1545–1556

    CAS  PubMed  Google Scholar 

  • Bonda DJ, Castellani RJ, Zhu X, Nunomura A, Lee HG, Perry G et al (2011) A novel perspective on tau in Alzheimer disease. Curr Alzheimer Res 8:639–642

    CAS  PubMed  Google Scholar 

  • Bourdel-Marchasson I, Delmas-Beauvieux MC, Peuchant E, Richard-Harston S, Decamps A, Reigner B et al (2001) Antioxidant defenses and oxidative stress markers in erythrocytes and plasma from normally nourished elderly Alzheimer patients. Age Aging 30:235–241

    CAS  Google Scholar 

  • Bowman GL (2012) Ascorbic acid, cognitive function, and Alzheimer’s disease: a current review and future direction. BioFactors 38:114–122

    CAS  PubMed Central  PubMed  Google Scholar 

  • Braak H, Braak E (1991) Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1:213–216

    CAS  PubMed  Google Scholar 

  • Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    CAS  PubMed  Google Scholar 

  • Buggia-Prevot V, Sevalle J, Rossner S, Checler F (2008) NFkB-dependent control of BACE1 promoter transactivation by Aβ42. J Biol Chem 283:10037–10047

    CAS  PubMed  Google Scholar 

  • Butterfield DA, Kanski J (2002) Methionine residue 35 is critical for the oxidative stress and neurotoxic properties of Alzheimer’s amyloid β-peptide 1–42. Peptides 23:1299–1309

    CAS  PubMed  Google Scholar 

  • Byun K, Bayarsaikhan E, Kim D, Kim CY, Mook-Jung I, Paek SH et al (2012a) Induction of neuronal death by microglial AGE-albumin: implications for Alzheimer’s disease. PLoS One 7(5):e37917

    CAS  PubMed Central  PubMed  Google Scholar 

  • Byun K, Bayarsaikhan E, Kim D, Son M, Hong J, Jeong GB et al (2012b) Activated microglial cells synthesize and secrete AGE-albumin. Anat Cell Biol 45:47–52

    PubMed Central  PubMed  Google Scholar 

  • Cai X, Golde T, Younkin S (1993) Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science 259:514–516

    CAS  PubMed  Google Scholar 

  • Cappai R, Barnham KJ (2007) Molecular determinants of Alzheimer’s disease Abeta peptide neurotoxicity. Future Neurol 2:397–409

    CAS  Google Scholar 

  • Caramelli P, Barbosa MT (2002) Como diagnosticar as quatro causas mais frequentes de demência? Rev Bras Psiquiatr 24:7–10

    Google Scholar 

  • Carubelli R, Schneider JE Jr, Pye QN, Floyd RA (1995) Cytotoxic effects of autoxidative glycation. Free Radic Biol Med 18:265–269

    CAS  PubMed  Google Scholar 

  • Castellani RJ, Lee H, Perry G, Smith MA (2006) Antioxidant protection and neurodegenerative disease: the role of amyloid-f3 and tau. Am J Alzheimers Dis Other Demen 21:126–130

    PubMed  Google Scholar 

  • Cente M, Filipcik P, Pevalova M, Novac M (2006) Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy. Eur J Neurosci 24:1085–1090

    PubMed  Google Scholar 

  • Chai GS, Jiang X, Ni ZF, Ma ZW, Xie AJ, Cheng XS et al (2013) Betaine attenuates Alzheimer-like pathological changes and memory deficits induced by homocysteine. J Neurochem 124:388–396

    CAS  PubMed  Google Scholar 

  • Chan A, Remington R, Kotyla E, Lepore A, Zemianek J, Shea TB (2010) A vitamin/nutriceutical formulation improves memory and cognitive performance in community-dwelling adults without dementia. J Nutr Health Aging 14(3):224–230

    CAS  PubMed  Google Scholar 

  • Chen L, Richardson JS, Caldwell JE, Ang LC (1994) Regional brain activity of free radical defense enzymes in autopsy samples from patients with Alzheimer’s disease and from nondemented controls. Int J Neurosci 75:83–90

    CAS  PubMed  Google Scholar 

  • Chen K, Kazachkov M, Yu PH (2007a) Effect of aldehydes derived from oxidative deamination and oxidative stress on beta-amyloid aggregation; pathological implications to Alzheimer’s disease. J Neural Transm 114:835–839

    CAS  PubMed  Google Scholar 

  • Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF, Yan SD (2007b) RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer’s disease. Curr Mol Med 7:735–742

    CAS  PubMed  Google Scholar 

  • Cherny RA, Legg JT, McLean CA, Fairlie DP, Huang X, Atwood CS et al (1999) Aqueous dissolution of Alzheimer’s disease abeta amyloid deposits by biometal depletion. J Biol Chem 274:23223–23228

    CAS  PubMed  Google Scholar 

  • Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA et al (2001) Treatment with a copper zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30:665–676

    CAS  PubMed  Google Scholar 

  • Christen Y (2000) Oxidative stress and Alzheimer disease. Am J Clin Nutr 71:621S–629S

    CAS  PubMed  Google Scholar 

  • Clauberg M, Joshi JG (1993) Regulation of serine protease activity by Al: implications for Alzheimer disease. Proc Natl Acad Sci USA 90:1009–1012

    CAS  PubMed Central  PubMed  Google Scholar 

  • Combs CK, Karlo JC, Kao S, Landreth GE (2001) β-amyloid stimulation of microglia and monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci 21:1179–1188

    CAS  PubMed  Google Scholar 

  • Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789

    CAS  PubMed  Google Scholar 

  • Cruz-Sánchez FF, Gironès X, Ortega A, Alameda F, Lafuente JV (2010) Oxidative stress in Alzheimer’s disease hippocampus: a topographical study. J Neurol Sci 299:163–167

    PubMed  Google Scholar 

  • Cummings JL, McRae T, Zhang R (2006) Donepezil-Sertraline Study Group. Effects of donepezil on neuropsyquiatric symptoms in patients with dementia and severe behavioral disorders. Am J Geriatr Psychiatry 14:605–612

    PubMed  Google Scholar 

  • Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K et al (2001) Alzheimer’s disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem 276:20466–20473

    CAS  PubMed  Google Scholar 

  • Dai X, Sun Y, Jiang Z (2006) Cu (II) potentiation of alzheimer Aβ1-40 cytotoxicity and transition on its secondary structure. Acta Biochim Biophys Sinica 38:765–772

    CAS  Google Scholar 

  • Danscher G, Stoltenberg M (2005) Zinc-specific autometallographic in vivo selenium methods: tracing of zinc-enriched (ZEN) terminals, ZEN pathways, and pools of zinc ions in a multitude of other ZEN cells. J Histochem Cytochem 53:141–153

    CAS  PubMed  Google Scholar 

  • De Strooper D, Saftig P, Craessmaerts K (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391:387–390

    PubMed  Google Scholar 

  • Disilvestro RA, Joseph E, Zhao S, Bomser J (2012) Diverse effects of a low dose supplement of lapidated curcumin in healthy middle aged people. Nutr J 11:79

    CAS  PubMed Central  PubMed  Google Scholar 

  • Drechsel DN, Hyman AA, Cobb MH, Kirschnner MW (1992) Modulation of the dynamic instability of tubulin assembly by microtubule-associated protein tau. Mol Cell Biol 10:1141–1154

    Google Scholar 

  • El-Agamey A, Lowe GM, McGarvey DJ, Mortensen A, Phillip DM, Truscott TG et al (2004) Carotenoid radical chemistry and antioxidant/pro-oxidant properties. Arch Biochem Biophys 430:37–48

    CAS  PubMed  Google Scholar 

  • Feng Y, Wang X (2012) Antioxidant therapies for Alzheimer’s disease. Oxid Med Cell Longev ID472932

  • Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M et al (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366:2112–2117

    PubMed Central  PubMed  Google Scholar 

  • Forbes JM, Soldatos G, Thomas MC (2005) Below the radar: advanced glycation end products that detour “around the side”. Is HbA1c not an accurate enough predictor of long term progression and glycaemic control in diabetes? Clin Biochem Rev 26:123–134

    PubMed Central  PubMed  Google Scholar 

  • Forlenza OV (2005) Tratamento Farmacológico da Doença de Alzheimer. Rev Psiq Clín 32:137–148

    Google Scholar 

  • Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462

    CAS  PubMed  Google Scholar 

  • Frederickson CJ, Giblin LJ III, Balaji RV, Masalha R, Frederickson CJ, Zeng Y et al (2006) Synaptic release of zinc from brain slices: factors governing release, imaging, and accurate calculation of concentration. J Neurosci Methods 154(1–2):19–29

    CAS  PubMed  Google Scholar 

  • Friedlich AL, Butcher LL (1994) Involvement of free oxygen radicals in beta-amyloidosis: a hypothesis. Neurobiol Aging 15:443–455

    CAS  PubMed  Google Scholar 

  • Friedlich AL, Lee JY, Van Groen T, Cherny RA, Volitakis I, Cole TB et al (2004) Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer’s disease. J Neurosci 24:3453–3459

    CAS  PubMed  Google Scholar 

  • Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA et al (2012) Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol 69(7):836–841

    PubMed Central  PubMed  Google Scholar 

  • Gasic-Milenkovic J, Loske C, Munch G (2003) Advanced glycation endproducts cause lipid peroxidation in the human neuronal cell line SH-SY5Y. J Alzheimers Dis 5:25–30

    CAS  PubMed  Google Scholar 

  • Gattaz WF, Forlenza OV, Talib LL, Barbosa NR, Bottino CM (2004) Platelet phospholipase A2 activity in Alzheimer´s disease and mild cognitive impairment. J Neural Transm 111:591–601

    CAS  PubMed  Google Scholar 

  • Glenner GG (1988) Alzheimer’s disease: its proteins and genes. Cell 52:307–308

    CAS  PubMed  Google Scholar 

  • Golde TE (2006) Disease modifying therapy for AD? J Neurochem 3:689–707

    Google Scholar 

  • Goodman Y, Mattson MP (1994) Secreted forms of β-amyloid precursor protein protect hippocampal neurons against amyloid β-peptide-induced oxidative injury. Exp Neurol 128:1–12

    CAS  PubMed  Google Scholar 

  • Goodman Y, Steiner M, Steiner S, Mattson MP (1994) Nordihydroguaiaretic acid protects hippocampal neurons against amyloid β-peptide toxicity, and attenuates free radical and calcium accumulation. Brain Res 654:171–176

    CAS  PubMed  Google Scholar 

  • Graeber MB, Kosel S, Grasbon-Frodi E, Moller HJ, Mehraein P (1998) Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D. Neurogenetics 1:223–228

    CAS  PubMed  Google Scholar 

  • Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3 beta in cellular signaling. Prog Neurobiol 65:391–426

    CAS  PubMed  Google Scholar 

  • Grodstein F, Chen J, Willet WC (2003) High dose antioxidant supplements and cognitive function in community-dwelling elderly women. Am J Clin Nutr 77:975–984

    CAS  PubMed  Google Scholar 

  • Grundke-Iqbal I, Fleming J, Tung YC, Lassmann H, Iqbal K, Joshi JG (1990) Ferritin is a component of the neuritic (senile) plaque in Alzheimer dementia. Acta Neuropathol 81:105–110

    CAS  PubMed  Google Scholar 

  • Gsell W, Conrad R, Hickethier M, Sofic E, Frolich L, Wichart I et al (1995) Decreased catalase activity but unchanged superoxide dismutase activity in brains of patients with dementia of Alzheimer type. J Neurochem 64:1216–1223

    CAS  PubMed  Google Scholar 

  • Guix FX, Raga Ill G, Bravo R, Nakaya T, Fabritiis G, Coma M et al (2009) Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation. Brain J Neurol 132:1335–1345

    Google Scholar 

  • Hager K, Kenklies M, McAfoose J, Engel J, Munch G (2007) Alpha-lipoic acid as a new treatment option for Alzheimer’s disease a 48 months follow-up analysis. J Neural Transm Suppl 72:189–193

    CAS  PubMed  Google Scholar 

  • Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine, 3rd edn. Oxford University Press, New York

    Google Scholar 

  • Hardy J (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci 20:154–159

    CAS  PubMed  Google Scholar 

  • Harman D, Eddy DE, Noffsinger J (1976) Free radical theory of aging: inhibition of amyloidosis in mice by antioxidants: possible mechanism. J Am Geriatr Soc 24:203–210

    CAS  PubMed  Google Scholar 

  • Hazel JR, Williams EE (1990) The role of alterations in membrane lipid composition in enabling physiological adaptation of organisms to their physical environment. Prog Lipid Res 29:167–227

    CAS  PubMed  Google Scholar 

  • Helson L (1984) The effect of intravenous vitamin E and menadiol sodium diphosphate on vitamin K dependent clotting factors. Thromb Res 35:11–18

    CAS  PubMed  Google Scholar 

  • Hensley K, Hall N, Subramaniam R, Cole P, Harris M, Aksenov M et al (1995) Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J Neurochem 65:2146–2156

    CAS  PubMed  Google Scholar 

  • Hernandez F, Avila J (2007) Tauopathies. Cell Mol Life Sci 64:2219–2233

    CAS  PubMed  Google Scholar 

  • Hidalgo FJ, Zamora R (2005) Interplay between the maillard reaction and lipid peroxidation in biochemical systems. Ann N Y Acad Sci 1043:284–289

    Google Scholar 

  • Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR et al (1999) Cu(II) potentiation of Alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 274:37111–37116

    CAS  PubMed  Google Scholar 

  • Huang X, Moir RD, Tanzi RE, Bush AI, Rogers JT (2004) Redox-active metals, oxidative stress, and Alzheimer’s disease pathology. Ann N Y Acad Sci 1012:153–163

    CAS  PubMed  Google Scholar 

  • Huebschmann AG, Regensteiner JG, Vlassara H, Reusch JE (2006) Diabetes and glicoxidation end products. Diabetes Care 29:1420–1432

    CAS  PubMed  Google Scholar 

  • Hutton M, Busfield F, Wragg M, Crook R, Pérez-Tur J, Clark RF (1996) Complete analysis of the presenilin 1 gene in early onset Alzheimer’s disease. Neuroreport 7:801–805

    CAS  PubMed  Google Scholar 

  • Hyman BT, Van Hoesen GW, Damasio AR (1990) Memory-related neural systems in Alzheimer’s disease: an anatomic study. Neurology 40:1721–1730

    CAS  PubMed  Google Scholar 

  • Ikeda T, Yamamoto K, Takahashi K (1992) Treatment of Alzheimer-type dementia with intravenous mecobalamin. Clin Ther 14:426–437

    CAS  PubMed  Google Scholar 

  • Ishrat T, Hoda MN, Khan MB, Yousuf S, Ahmad M, Khan MM et al (2009) Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer’s type (SDAT). Eur Neuropsychopharmacol 19:636–647

    CAS  PubMed  Google Scholar 

  • Ittner LM, Gotz J (2011) Amyloid-β and tau—a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 12:67–72

    Google Scholar 

  • Jakus V, Rietbrock N (2004) Advanced glycation end products and the progress of diabetic vascular complications. Physiol Res 53:131–142

    CAS  PubMed  Google Scholar 

  • Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH et al (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736

    CAS  PubMed  Google Scholar 

  • Keller JN, Schmitt FA, Scheff SW, Ding Q, Chen Q, Butterfield DA et al (2005) Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 64:1152–1156

    CAS  PubMed  Google Scholar 

  • Kim H, Evans I, Smallwood R, Holcombe M, Qwamstrom EE (2010) NIK and IKK interdependence in NF-kB signaling-flux analysis of regulation. J Biosyst 99:140–149

    CAS  Google Scholar 

  • Kimura T, Takamatsu J, Araki N, Goto M, Kondo A, Miyakawa T et al (1995) Are advanced glycation end-products associated with amyloidosis in Alzheimer’s disease? Neuroreport 6:866–868

    CAS  PubMed  Google Scholar 

  • Kovac A, Zilka N, Kazmerova Z, Cente M, Zilkova M, Novac M (2011) Misfolded truncated protein τ induces innate immune response via MAPK pathway. J Immunol 187:2723–2739

    Google Scholar 

  • Kriete A, Mayo KL (2009) Atypical pathways of NF-kB activation and aging. J Exp Gerontol 44:250–255

    CAS  Google Scholar 

  • Kuhla B, Loske C, De Arriba SG, Schinzel R, Huber J, Münch G (2004) Differential effects of “advanced glycation endproducts” and β-amyloid peptide on glucose utilization and ATP levels in the neuronal cell line SH-SY5Y. J Neural Transm 111:427–439

    CAS  PubMed  Google Scholar 

  • Lanctôt KL, Herrmann N, Loulou MM (2003) Correlates of response to acetylcholinesterase inhibitor therapy in Alzheimer´s disease. J Psychiatry Neurosci 28:13–26

    PubMed Central  PubMed  Google Scholar 

  • Lapolla A, Fedele D, Traldi P (2005) Glyco-oxidation in diabetes and related diseases. Clin Chim Acta 357:236–250

    CAS  PubMed  Google Scholar 

  • Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY (2002) Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice. Proc Natl Acad Sci USA 99:7705–7710

    CAS  PubMed Central  PubMed  Google Scholar 

  • Leslie RD, Beyan H, Sawtell P, Boehm BO, Spector TD, Snieder H (2003) Level of an advanced glycated end product is genetically determined. A study of normal twins. Diabetes 52:2441–2444

    CAS  PubMed  Google Scholar 

  • Li X, Song L, Jope RS (1996) Cholinergic stimulation of AP-1 and NFKB transcription factors is differentially sensitive to oxidative stress in sh-sy5y neuroblastoma: relationship to phosphoinositide hydrolysis. J Neurosci 16:5914–5922

    CAS  PubMed  Google Scholar 

  • Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM (2001) The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21:8370–8377

    CAS  PubMed  Google Scholar 

  • Lin L (2006) RAGE on the toll road? Cell Mol Immunol 3:351–358

    CAS  PubMed  Google Scholar 

  • Lo ACY, Haass C, Wagner SL, Teplow DB, Sisodia SS (1994) Metabolism of the “Swedish” amyloid precursor protein variant in Madin-Darby canine kidney cells. J Biol Chem 269:22099–22104

    Google Scholar 

  • Lohr JB (1991) Oxygen radicals and neuropsychiatric illness. Arch Gen Psychiatry 48:1097–1106

    CAS  PubMed  Google Scholar 

  • Lovell MA, Ehmann WD, Butler SM, Markesbery WR (1995) Elevated thiobarbituric acid reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology 45:1594–1601

    CAS  PubMed  Google Scholar 

  • Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998a) Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci 158:47–52

    CAS  PubMed  Google Scholar 

  • Lovell MA, Xie C, Markesbery WR (1998b) Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer’s disease. Neurology 51:1562–1566

    CAS  PubMed  Google Scholar 

  • Lowenberg K, Waggoner R (1934) Familial organic psychosis (Alzheimer’s type). Arch Neurol Psychiatry 31:737–754

    Google Scholar 

  • Lue LF, Walker DG, Brachova L, Beach TG, Rogers J, Schmidt AM et al (2001) Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism. Exp Neurol 171:29–45

    CAS  PubMed  Google Scholar 

  • Mann DMA (1985) The neuropathology of Alzheimer’s disease: a review with pathogenetic, aetiological and therapeutic considerations. Mech Ageing 31:213–255

    CAS  Google Scholar 

  • Marcus DL, Thomas C, Rodríguez C, Simberkoff K, Tsai JS, Strafaci JA et al (1998) Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease. Exp Neurol 150:40–44

    CAS  PubMed  Google Scholar 

  • Markesbery WR, Kryscio RJ, Lovell MA, Morrow JD (2005) Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment. Ann Neurol 58:730–735

    CAS  PubMed  Google Scholar 

  • Masaki KH, Losonczy KG, Izmirlian G, Foley DJ, Ross GW, Petrovitch H et al (2000) Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 54:1265–1272

    CAS  PubMed  Google Scholar 

  • McCaddon A, Hudson P, Hill D, Barber J, Lloyd A, Davies G et al (2003) Alzheimer’s disease and total plasma aminothiols. Biol Psychiatry 53:254–260

    CAS  PubMed  Google Scholar 

  • McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM (2006) A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 354:2764–2772

    CAS  PubMed  Google Scholar 

  • Meade SJ, Miller AG, Gerrard JA (2003) The role of dicarbonyl compounds in non-enzymatic crosslinking: a structure–activity study. Bioorg Med Chem 11:853–862

    CAS  PubMed  Google Scholar 

  • Mecocci P, MacGarvey U, Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–751

    CAS  PubMed  Google Scholar 

  • Monnier VM (2003) Intervention against the Maillard reaction in vivo. Arch Biochem Biophys 419:1–15

    CAS  PubMed  Google Scholar 

  • Moreira PI, Harris PL, Zhu X, Santos MS, Oliveira CR, Smith MA et al (2007) Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts. J Alzheimers Dis 12:195–206

    CAS  PubMed  Google Scholar 

  • Morris RG, Salmon DP (2007) The centennial of Alzheimer’s disease and the publication of “Über Eine Eigenartige Erkankung Der Hirnrinde” by Alois Alzheimer. Cortex 43:821–825

    PubMed  Google Scholar 

  • Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS (2002) Vitamin E and cognitive decline in older persons. Arch Neurol 59:1125–1132

    PubMed  Google Scholar 

  • Mullarkey CJ, Edelstein D, Brownlee M (1990) Free radical generation by early glycation products: a mechanism for accelerated atherogenesis in diabetes. Biochem Biophys Res Commun 173:932–939

    CAS  PubMed  Google Scholar 

  • Muller WE, Kosh S, Eckert A, Hartmann H, Scheuer K (1995) β-amyloid peptide decreases membrane fluidity. Brain Res 674:33–36

    Google Scholar 

  • Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R et al (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. JAMA 283(8):1007–1015

    CAS  PubMed  Google Scholar 

  • Munch G, Thorne J, Foley P, Schinzel R, Riederer P (1997) Advanced glycation end products in aging and Alzheimer’s disease. Brain Res Rev 23:134–143

    CAS  PubMed  Google Scholar 

  • Münch G, Schinzel R, Loske C, Wong A, Durany N, Li JJ et al (1998) Alzheimer’s disease synergistic effects of glucose deficit: oxidative stress and advanced glycation endproducts. J Neural Transm 105:439–461

    PubMed  Google Scholar 

  • Münch G, Deuther-Conrad W, Gasic-Milenkovic J (2002) Glycoxidative stress creates a vicious cycle of neurodegeneration in Alzheimer’s disease a target for neuroprotective treatment strategies? J Neural Transm 62:303–307

    Google Scholar 

  • Muscat S, Pelka J, Hegele J, Weigle B, Münch G, Pischet-Srieder M (2007) Coffee and Maillard products activate NF-kappa B in macrophages via H2O2 production. Mol Nutr Food Res 51:525–535

    CAS  PubMed  Google Scholar 

  • Nitrini R (1999) Epidemiologia da doença de Alzheimer no Brasil. Rev Psiquiatr Clin 26:262–267

    Google Scholar 

  • Nitsch RM, Slack BE, Farber SA, Schulz JG, Deng M, Kim C et al (1994) Regulation of proteolytic processing of the amyloid β-protein precursor of Alzheimer’s disease in transfected cell lines and in brain slices. J Neural Transm 44:21–27

    CAS  Google Scholar 

  • Ortwerth BJ, James H, Simpson G, Linetsky M (1998) The generation of superoxide anions in glycation reactions with sugars, ozone, and 3-deoxyosones. Biochem Biophys Res Commun 245:161–165

    CAS  PubMed  Google Scholar 

  • Packer MA, Murphy MP (1994) Peroxynitrite causes efflux from mitochondria which is prevented by cyclosporin A. FEBS Lett 345:237–240

    CAS  PubMed  Google Scholar 

  • Packer MA, Scarlett JL, Martin SW, Murphy MP (1997) Induction of the mitochondrial permeability transition by peroxynitrite. Biochem Soc Trans 25:909–914

    CAS  PubMed  Google Scholar 

  • Padurariu M, Ciobica A, Hritcu L, Stoica B, Bild W, Stefanescu C (2010) Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer’s disease. Neurosci Lett 469:6–10

    CAS  PubMed  Google Scholar 

  • Payami H, Kaye J, Heston LL, Bird TD, Schellenberg GD (1993) Apolipoprotein E genotypes and Alzheimer’s disease. Lancet 342:737–738

    Google Scholar 

  • Peppa M, Uribarri J, Vlassara H (2003) Glucose, advanced glycation end products, and diabetes complications: what is new and what works. Clin Diabetes 21:186–187

    Google Scholar 

  • Perkins AJ, Hendrie HC, Callahan CM, Gao S, Unverzagt FW, Xu Y et al (1999) Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey. Am J Epidemiol 150:37–44

    CAS  PubMed  Google Scholar 

  • Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH (1978) Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 25:1457–1459

    Google Scholar 

  • Persson T, Popescu BO, Cedazo-Minguez A (2014) Oxidative stress in Alzheimer’s disease: why did antioxidant therapy fail. Oxid Med Cell Longev ID427318

  • Perumal AS, Gopal VB, Tordzro WK, Cooper TB, Cadet JL (1992) Vitamin E attenuates the toxic effects of 6-hydroxydopamine on free radical scavenging systems in rat brain. Brain Res Bull 29:699–701

    CAS  PubMed  Google Scholar 

  • Prasad KN, Cole WC, Prasad KC (2002) Risk factors for Alzheimer’s disease: role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment. J Am Coll Nutr 21:506–522

    CAS  PubMed  Google Scholar 

  • Pratico D, Sung S (2004) Lipid peroxidation and oxidative imbalance: early functional event in Alzheimer’s disease. J Alzheimers Dis 6:171–175

    CAS  PubMed  Google Scholar 

  • Pratico D, Clark CM, Liun F, Lee VY, Trojanowsk JQ (2002) Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch Neurol 59:972–976

    PubMed  Google Scholar 

  • Price DL (1986) New perspectives on Alzheimer’s disease. Annu Rev Neurosci 9:489–512

    CAS  PubMed  Google Scholar 

  • Prince M, Bryce R, Ferri C (2011) The benefits of early diagnosis and intervention, executive summary. In: Alzheimer’s Disease International, World Alzheimer Report 2011, London

  • Quinn JF, Bussiere JR, Hammond RS, Montine TJ, Henson E, Jones RE et al (2007) Chronic dietary α-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol Aging 28:213–215

    CAS  PubMed  Google Scholar 

  • Quintana C, Bellefqih S, Laval JY, Guerquin-Kern JL, Wu TD, Avila J et al (2006) Study of the localization of iron, ferritin, and hemosiderin in Alzheimer’s disease hippocampus by analytical microscopy at the subcellular level. J Struct Biol 153:42–54

    CAS  PubMed  Google Scholar 

  • Rao KSJ, Rao RV, Shanmugavelu P, Menon RB (1999) Trace elements in Alzheimer’s disease brain: a new hypothesis. Alzheimers Rep 2:241–246

    Google Scholar 

  • Reddy PH (2011) Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer’s disease. Brain Res 1415:136–148

    CAS  PubMed Central  PubMed  Google Scholar 

  • Regland B, Gottfries CG, Oreland L (1991) Vitamin B12-induced reduction of platelet monoamine oxidase activity in patients with dementia and pernicious anaemia. Eur Arch Psychiatry Clin Neurosci 240:288–291

    CAS  PubMed  Google Scholar 

  • Religa D, Strozyk D, Cherny RA, Volitakis I, Haroutunian V, Winblad B et al (2006) Elevated cortical zinc in Alzheimer disease. Neurology 67:69–75

    CAS  PubMed  Google Scholar 

  • Richter T, Munch G, Luth HJ, Arendt T, Kientsch-Engel R, Stahl P et al (2005) Immunochemical crossreactivity of antibodies specific for “advanced glycation end products” with “advanced lipoxidation endproducts”. Neurobiol Aging 26:465–474

    CAS  PubMed  Google Scholar 

  • Rinaldi P, Polidori MC, Metasstasio A (2003) Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol Aging 24:915–919

    CAS  PubMed  Google Scholar 

  • Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beiji M et al (2012) Oral curcumin for Alzheimer’s disease: tolerability and efficacy in a 24-week randomized, double-blind, placebo-controlled study. Alzheimers Res Ther 4(5):43

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L et al (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer’s disease: biochemical and clinical responses in a pilot phase 2 clinical trial. Arch Neurol 60:1685–1691

    PubMed  Google Scholar 

  • Rogers JT, Randall JD, Cahill CM, Eder PS, Huang X, Gunshin H et al (2002) An iron-responsive element type II in the 5′ untranslated region of the Alzheimer’s amyloid precursor protein transcript. J Biol Chem 277:45518–45528

    CAS  PubMed  Google Scholar 

  • Russ C, Lovestone S, Powell JF (2001) Identification of sequence variants and analysis of the role of the glycogen synthase kinase 3 beta gene and promoter in late onset Alzheimer´s disease. Mol Psychiatry 6:320–324

    CAS  PubMed  Google Scholar 

  • Sagara YR, Dargusch R, Klier FG, Schubert D, Behl C (1996) Increased antioxidant enzyme activity in amyloid beta protein-resistant cells. J Neurosci 16:497–505

    CAS  PubMed  Google Scholar 

  • Saitoh T, Sundsmo M, Roch J, Ximura M, Cole G, Schubert D et al (1989) Secreted form of amyloid β-protein precursor is involved in the growth regulation of fibroblasts. Cell 58:615–622

    CAS  PubMed  Google Scholar 

  • Sano M, Ernesto C, Thomas RG (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med 336:1216–1222

    CAS  PubMed  Google Scholar 

  • Sato T, Shimogaito N, Wu X, Kikuchi S, Yamagishi S, Takeuchi M (2006) Toxic advanced glycation end products (TAGE) theory in Alzheimer’s disease. Am J Alzheimers Dis Other Demen 2:197–208

    Google Scholar 

  • Schlief ML, Craig AM, Gitlin JD (2005) NMDA receptor activation mediates copper homeostasis in hippocampal neurons. J Neurosci 25:239–246

    CAS  PubMed  Google Scholar 

  • Schlief ML, West T, Craig AM, Holtzman DM, Gitlin JD (2006) Role of the Menkes copper-transporting ATPase in NMDA receptor mediated neuronal toxicity. Proc Natl Acad Sci USA 103:14919–14924

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schubert D, Jin LW, Saitoh T, Cole G (1989) The regulation of amyloid β-protein precursor secretion and its modulatory role in cell adhesion. Neuron 3:689–694

    CAS  PubMed  Google Scholar 

  • Schubert D, Kimura H, Maher P (1992) Growth factors and vitamin E modify neuronal glutamate toxicity. Proc Natl Acad Sci USA 89:8264–8267

    CAS  PubMed Central  PubMed  Google Scholar 

  • Selkoe DJ (1993) Physiological production of the β-amyloid protein and the mechanism of Alzheimer’s disease. Trends Neurosci 16:403–409

    CAS  PubMed  Google Scholar 

  • Sherrington RE, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375:754–760

    CAS  PubMed  Google Scholar 

  • Siedlak SL, Casadesus G, Webber KM, Pappolla MA, Atwood CS, Smith MA et al (2009) Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer’s disease. Free Radic Res 43:156–164

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sinclair AJ, Bayer AJ, Johnston J, Warner C, Maxwell SRJ (1998) Altered plasma antioxidant status in subjects with Alzheimer’s disease and vascular dementia. Int J Geriatr Psychiatry 13:840–845

    CAS  PubMed  Google Scholar 

  • Sinha M, Saha A, Basu S, Pal K, Chakrabarti S (2010) Aging and antioxidants modulate rat brain levels of homocysteine and dehydroepiandrosterone sulphate (DHEA-S): implications in the pathogenesis of Alzheimer’s disease. Neurosci Lett 483:123–126

    CAS  PubMed  Google Scholar 

  • Smith MA, Perry G (1994) Alzheimer disease: an imbalance of proteolytic regulation? Med Hypotheses 42:277–279

    CAS  PubMed  Google Scholar 

  • Smith MA, Sayre LM (1995) Radical AGEing in Alzheimer disease. Trends Neurosci 18:172–176

    CAS  PubMed  Google Scholar 

  • Smith CD, Carney JM, Starke-Reed PE, Oliver CN, Stadtman ER, Floyd RA et al (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and Alzheimer disease. Proc Natl Acad Sci USA 88:10540–10543

    CAS  PubMed Central  PubMed  Google Scholar 

  • Smith MA, Petot GJ, Perry G (1999) Diet and oxidative stress: a novel synthesis of epidemiological data on Alzheimer’s disease. J Alzheimers Dis 1:203–206

    CAS  PubMed  Google Scholar 

  • Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D et al (2011) Advanced glycation end products and their receptor RAGE in Alzheimer’s disease. Neurobiol Aging 32:763–777

    CAS  PubMed  Google Scholar 

  • St George-Hyslop P (1995) Genetic determinants of Alzheimer disease. Prog Clin Biol Res 393:139–145

    CAS  PubMed  Google Scholar 

  • Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM (2002) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 156:1051–1063

    CAS  PubMed Central  PubMed  Google Scholar 

  • Stocker R (1994) Lipoprotein oxidation: mechanistic aspects, methodological approaches and clinical relevance. Curr Opin Lipidol 5:422–433

    CAS  PubMed  Google Scholar 

  • Subbarao KV, Richardson JS, Ang LC (1990) Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro. J Neurochem 55:342–345

    CAS  PubMed  Google Scholar 

  • Suchy J, Chan A, Shea TB (2009) Dietary supplementation with a combination of α-lipoic acid, acetyl-L-carnitine, glycerophosphocoline, docosahexaenoic acid, and phosphatidylserine reduces oxidative damage to murine brain and improves cognitive performance. Nutr Res 29:70–74

    CAS  PubMed  Google Scholar 

  • Suh Y, Checler F (2002) Amyloid precursor protein, presenilins, and α-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacol Rev 54:469–525

    CAS  PubMed  Google Scholar 

  • Sultan A, Nesslany F, Violet M, Bégard S, Loyens A, Talahari S et al (2011) Nuclear tau, a key player in neuronal DNA protection. J Biol Chem 286:4566–4575

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sultana R, Mecocci P, Mangialasche F, Cecchetti R, Baglioni M, Butterfield A (2011) increased protein and lipid oxidative damage in mitochondria isolated from lymphocytes from patients with Alzheimer’s disease: insights into the role of oxidative stress in Alzheimer’s disease and initial investigations into a potential biomarker for this dementing disorder. J Alzheimers Dis 24:77–84

    CAS  PubMed  Google Scholar 

  • Sung S, Yao Y, Uryu K, Yang H, Lee VMY, Trojanowski JQ et al (2004) Early Vitamin E supplementation in young but not aged mice reduces Aβ levels and amyloid deposition in a transgenic model of Alzheimer’s disease. FASEB J 18(2):323–325

    CAS  PubMed  Google Scholar 

  • Takeuchi M, Yamagishi S (2004) TAGE (toxics AGEs) hypothesis in various chronic diseases. Med Hypotheses 63:449–452

    CAS  PubMed  Google Scholar 

  • Takeuchi M, Sato T, Takino J, Kobayashi Y, Furuno S, Kikuchi S et al (2007) Diagnostic utility of serum or cerebrospinal fluid levels of toxic advanced glycation end-products (TAGE) in early detection of Alzheimer’s disease. Med Hypotheses 69:1358–1366

    CAS  PubMed  Google Scholar 

  • Tanzi RE, Kovacs DM, Kim TW, Moir RD, Guenette SY, Wasco W (1996) The gene defects responsible for familial Alzheimer’s disease. Neurobiol Dis 3:159–168

    CAS  PubMed  Google Scholar 

  • Terry RD (1985) Alzheimer’s disease. In: Davis RL, Robertson DM (eds) Textbook of neuropathology. Williams and Wilkins, Baltimore, pp 824–841

    Google Scholar 

  • Thomas T, Thomas G, McLendon C, Sutton T, Mullan M (1996) Beta-amyloid mediated vasoactivity and vascular endothelial damage. Nature 380:168–171

    CAS  PubMed  Google Scholar 

  • Thornalley PJ (2003) The enzymatic defense against glycation in health, disease and therapeutics: a symposium to examine the concept. Biochem Soc Trans 6:1341–1342

    Google Scholar 

  • Truzzi A, Laks J (2005) Doença de Alzheimer esporádica de início precoce. Rev Psiquiatr Clín 32(1):43–46

    Google Scholar 

  • Uwano C, Suzuki M, Aikawa T, Ebihara T, Une K, Tomita N et al (2012) Rivastigmine dermal patch solves eating problems in an individual with advanced Alzheimer’s disease. J Am Geriatr Soc 60(10):1979–1980

    PubMed  Google Scholar 

  • Valente T, Gella A, Fernàndez-Busquets X, Unzeta M, Durany N (2010) Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol Dis 37:67–76

    CAS  PubMed  Google Scholar 

  • Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J (2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 266:37–56

    CAS  PubMed  Google Scholar 

  • Valla J, Berndt JD, Gonzalez-Lima F (2001) Energy hypometabolism in posterior cingulated cortex of Alzheimer’s patients: superficial laminar cytochrome oxidase associated with disease duration. J Neurosci 21:4923–4930

    CAS  PubMed  Google Scholar 

  • Vas CJ, Rajikumar S, Tanyakitpisal P, Chandra V (2001) Alzheimer’s disease: the brain killer. World Health Organization, Regional Office for South-East Asia, New Delhi

    Google Scholar 

  • Vellas B, Coley N, Ousset PJ, Berrut G, Dartigues JF, Dubois B et al (2012) Long term use of standardized ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomized placebo-controlled trial. Lancet Neurol 11(10):851–859

    CAS  PubMed  Google Scholar 

  • Vlassara H, Palace MR (2002) Diabetes and advanced glycation end products. J Intern Med 251:87–101

    CAS  PubMed  Google Scholar 

  • Wataya T, Nunomura A, Smith MA, Siedlak SL, Harris PL, Shimohama S et al (2002) High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. J Biol Chem 277:4644–4648

    CAS  PubMed  Google Scholar 

  • Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle AW, Delon MR (1982) Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215:1237–1239

    CAS  PubMed  Google Scholar 

  • Wimo A, Prince M (2010) The global economic impact of dementia. In: Alzheimer’s Disease International, World Alzheimer Report 2010, London

  • Xue J, Rai V, Frolov S, Singer D, Chabierski S, Xie J et al (2011) Advanced glycation end product (AGE) recognition by the receptor for AGEs (RAGE). Structure 19:722–732

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS et al (1994) Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci USA 91:7787–7791

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yan SD, Fu J, Soto C, Chen X, Zhu H, Al-Mohanna F et al (1997) An intracellular protein that binds amyloid-betapeptide and mediates neurotoxicity in Alzheimer’s disease. Nature 389:689–695

    CAS  PubMed  Google Scholar 

  • Yang SG, Wang WY, Ling TJ, Feng Y, Du XT, Zhang X et al (2010) α-Tocopherol quinone inhibits β-amyloid aggregation and cytotoxicity, disaggregates preformed fibrils and decreases the production of reactive oxygen species, NO and inflammatory cytokines. Neurochem Int 57:914–922

    CAS  PubMed  Google Scholar 

  • Yonekura H, Yamamoto Y, Sakurai S, Watanabe T, Yamamoto H (2005) Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular injury. J Pharmacol Sci 97:305–311

    CAS  PubMed  Google Scholar 

  • Zafrilla P, Mulero J, Xandri JM, Santo E, Caravaca G, Morillas JM (2006) Oxidative stress in Alzheimer patients in different stages of the disease. Curr Med Chem 13:1075–1083

    CAS  PubMed  Google Scholar 

  • Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5:863–873

    CAS  PubMed  Google Scholar 

  • Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol 3:219–226

    CAS  PubMed  Google Scholar 

  • Zinser EG, Hartmann T, Grimm MOW (2007) Amyloid beta-protein and lipid metabolism. Biochem Biophys Acta 1768:1991–2001

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

All authors are grateful to Pró-Reitoria de Pesquisa e Pós-Graduação da Universidade Federal do Pará (PROPESP/UFPA) and to Fundação de Amparo e Desenvolvimento da Pesquisa (FADESP) for providing funding for editorial expenses.

Author information

Authors and Affiliations

  1. Oxidative Stress Research Lab, Institute of Biological Sciences (LAPEO – ICB), Federal University of Pará, Av. Augusto Correa, 01, Belém, PA, 66075-110, Brazil

    Michelli Erica Souza Ferreira, Amanda Soares de Vasconcelos, Aline da Silva Barbosa, Antonio Rafael Quadros Gomes & Sandro Percário

  2. Pharmacy Department, Institute of Health Sciences, Federal University of Pará, Av. Augusto Correa, 01, Belém, PA, 66075-110, Brazil

    Thyago da Costa Vilhena, Thiago Leite da Silva & Maria Fani Dolabela

Authors
  1. Michelli Erica Souza Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amanda Soares de Vasconcelos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thyago da Costa Vilhena
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thiago Leite da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aline da Silva Barbosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonio Rafael Quadros Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maria Fani Dolabela
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sandro Percário
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sandro Percário.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ferreira, M.E.S., de Vasconcelos, A.S., da Costa Vilhena, T. et al. Oxidative Stress in Alzheimer’s Disease: Should We Keep Trying Antioxidant Therapies?. Cell Mol Neurobiol 35, 595–614 (2015). https://doi.org/10.1007/s10571-015-0157-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-015-0157-y

Keywords

Search

Navigation