Mitochondria and antioxidant targeted therapeutic strategies for Alzheimer's disease

Journal of Alzheimer's Disease

Volumn 20, Issue SUPPL.2, 2010, Pages

  Dumont, Magali ^a   Lin, Michael T ^a   Beal, M Flint ^a  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

Alzheimer's disease; antioxidants; mitochondria; oxidative stress; therapeutic strategies; transgenic mice

Indexed keywords

2 OXOGLUTARIC ACID; ALPHA TOCOPHEROL; AMINE OXIDASE (FLAVIN CONTAINING) ISOENZYME B; ASCORBIC ACID; BETA CAROTENE; BLUEBERRY EXTRACT; CURCUMIN; CYTOCHROME C OXIDASE; DIMEBON; FLAVONOID; FREE RADICAL; GLUTATHIONE; IDEBENONE; MANGANESE SUPEROXIDE DISMUTASE; MELATONIN; MITOCHONDRIAL DNA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PIOGLITAZONE; RESVERATROL; RETINOL; SELEGILINE; SELENIUM;

ALZHEIMER DISEASE; AMNESIA; CELL VIABILITY; DIET SUPPLEMENTATION; HUMAN; MITOCHONDRIAL TOXICITY; MORTALITY; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN EXPRESSION; REVIEW;

EID: 77956207871     PISSN: 13872877     EISSN: None     Source Type: Journal    
DOI: 10.3233/JAD-2010-100507     Document Type: Review

References (119)

1. Moreira PI, Nunomura A, Nakamura M, Takeda A, Shenk JC, Aliev G, Smith MA, Perry G (2008) Nucleic acid oxidation in Alzheimer disease. Free Radic Biol Med 44, 1493-1505.
2. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Bal- raj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60, 759-767.
3. de Leon MJ, Mosconi L, Li J, Schmechel D.E.anti S, Yao Y, Tsui WH, Pirraglia E, Rich K, Javier E, Brys M, Glodzik L, Switalski R, Saint Louis LA, Pratico D (2007) Longitudinal CSF iso- prostane and MRI atrophy in the progression to AD. J Neurol 254, 1666-1675.
4. Montine TJ, Quinn J, Kaye J, Morrow JD (2007) F(2)- isoprostanes as biomarkers of late-onset Alzheimer's disease. J Mol Neurosci 33, 114-119.
5. Ringman JM, Younkin SG, Pratico D, Seltzer W, Cole GM, Geschwind DH, Rodriguez-Agudelo Y, Schaffer B, Fein J, Sokolow S, Rosario ER, Gylys KH, Varpetian A, Medina LD, Cummings JL (2008) Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 71, 85-92.
6. Lovell MA, Markesbery WR (2007) Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease. Nucleic Acids Res 35, 7497-7504.
7. Lovell MA, Markesbery WR (2008) Oxidatively modified RNA in mild cognitive impairment. Neurobiol Dis 29, 169175.
8. Butterfield DA, Reed TT, Perluigi M, De Marco C, Coccia R, Keller JN, Markesbery WR, Sultana R (2007) Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer's disease. Brain Res 1148, 243-248.
9. Pratico D, Clark CM, Liun F, Rokach J, Lee VY, Trojanowski JQ (2002) Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch Neurol 59, 972-976.
10. Keller JN, Schmitt FA, Scheff SW, Ding Q, Chen Q, Butter- field DA, Markesbery WR (2005) Evidence of increased ox- idative damage in subjects with mild cognitive impairment. Neurology 64, 1152-1156.
11. Petersen RC, Roberts RO, Knopman DS, Boeve BF, Geda YE, Ivnik RJ, Smith GE, Jack CR, Jr. (2009) Mild cognitive impairment: ten years later. Arch Neurol 66, 1447-1455.
12. Jicha GA, Parisi JE, Dickson DW, Johnson K, Cha R, Ivnik RJ, Tangalos EG, Boeve BF, Knopman DS, Braak H, Pe- tersen RC (2006) Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol 63, 674-681.
13. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B (2001) Current concepts in mild cognitive impairment. Arch Neurol 58, 1985-1992.
14. Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin EH, Berg L (2001) Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 58, 397-405.
15. Pratico D, Uryu K, Leight S, Trojanoswki JQ, Lee VM (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neu- rosci 21, 4183-4187.
16. Abdul HM, Sultana R, St Clair DK, Markesbery WR, But- terfield DA (2008) Oxidative damage in brain from human mutant APP/PS-1 double knock-in mice as a function of age. Free Radic Biol Med 45, 1420-1425.
17. Resende R, Moreira PI, Proenca T, Deshpande A, Busciglio J, Pereira C, Oliveira CR (2008) Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radic Biol Med 44, 2051-2057.
18. Quiroz-Baez R, Rojas E, Arias C (2009) Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of alpha-, beta- and gamma-secretase expression. Neurochem Int 55, 662-670.
19. Chen X, Stern D, Yan SD (2006) Mitochondrial dysfunction and Alzheimer's disease. Curr Alzheimer Res 3, 515-520.
20. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, At- wood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shi- mohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Pe- tersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer's disease. J Neurosci 21, 3017-3023.
21. Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA (2009) S-nitrosylation of Drp1 mediates beta- amyloid-related mitochondrial fission and neuronal injury. Science 324, 102-105.
22. Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, Zhu X (2009) Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. J Neurosci 29, 9090-9103.
23. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30, 572-580.
24. Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity ofspines and synapses. Cell 119, 873-887.
25. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15, 1437-1449.
26. Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach M, Leuner K, Eckert A, Muller WE (2009) Mito- chondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 30, 1574-1586.
27. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brin- ton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 106, 1467014675.
28. Gibson GE, Blass JP, Beal MF, Bunik V (2005) The alpha- ketoglutarate-dehydrogenase complex: a mediator between mitochondria and oxidative stress in neurodegeneration. Mol Neurobiol 31, 43-63.
29. Gibson GE, Zhang H, Sheu KF, Bogdanovich N, Lindsay JG, Lannfelt L, Vestling M, Cowburn RF (1998) Alpha- ketoglutarate dehydrogenase in Alzheimer brains bearing the APP670/671 mutation. Ann Neurol 44, 676-681.
30. Butterworth RF, Besnard AM (1990) Thiamine-dependent enzyme changes in temporal cortex of patients with Alzheimer's disease. Metab Brain Dis 5, 179-184.
31. Mastrogiacomo F, Bergeron C, Kish SJ (1993) Brain alpha- ketoglutarate dehydrogenase complex activity in Alzheimer's disease. J Neurochem 61, 2007-2014.
32. Gibson GE, Sheu KF, Blass JP, Baker A, Carlson KC, Harding B, Perrino P (1988) Reduced activities of thiamine- dependent enzymes in the brains and peripheral tissues of patients with Alzheimer's disease. Arch Neurol 45, 836-840.
33. Karuppagounder SS, Xu H, Shi Q, Chen LH, Pedrini S, Pech- man D, Baker H, Beal MF, Gandy SE, Gibson GE (2009) Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model. Neurobiol Aging 30, 1587-1600.
34. Dumont M, Ho DJ, Calingasan NY, Xu H, Gibson G, Beal MF (2009) Mitochondrial dihydrolipoyl succinyltransferase deficiency accelerates amyloid pathology and memory deficit in a transgenic mouse model of amyloid deposition. Free Radic Biol Med 47, 1019-1027.
35. Li F, Calingasan NY, Yu F, Mauck WM, Toidze M, Almeida CG, Takahashi RH, Carlson GA, Flint Beal M, Lin MT, Gouras GK (2004) Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J Neurochem 89, 1308-1312.
36. Melov S, Adlard PA, Morten K, Johnson F, Golden TR, Hin- erfeld D, Schilling B, Mavros C, Masters CL, Volitakis I, Li QX, Laughton K, Hubbard A, Cherny RA, Gibson B, Bush AI (2007) Mitochondrial oxidative stress causes hyperphos- phorylation of tau. PLoS ONE 2, e536.
37. Esposito L, Raber J, Kekonius L, Yan F, Yu GQ, Bien-Ly N, Puolivali J, Scearce-Levie K, Masliah E, Mucke L (2006) Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J Neurosci 26, 5167-5179.
38. Dumont M, Wille E, Stack C, Calingasan NY, Beal MF, Lin MT (2009) Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer's disease. FASEBJ 23, 2459-2466.
39. Massaad CA, Washington TM, Pautler RG, Klann E (2009) Overexpression of SOD-2 reduces hippocampal superox- ide and prevents memory deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U SA 106, 1357613581.
40. Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat Med 14, 1097-1105.
41. Du H, Guo L, Zhang W, Rydzewska M, Yan S (2009) Cy- clophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model. Neurobiol Aging, in press.
42. Sung S, Yao Y, Uryu K, Yang H, Lee VM, Trojanowski JQ, Pratico D (2004) Early vitamin E supplementation in young but not aged mice reduces Abeta levels and amyloid deposition in a transgenic model of Alzheimer's disease. FASEB J 18, 323-325.
43. Harrison FE, Allard J, Bixler R, Usoh C, Li L, May JM, McDonald MP (2009) Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice. Nutr Neurosci 12, 203-218.
44. Nishida Y, Ito S, Ohtsuki S, Yamamoto N, Takahashi T, Iwa- ta N, Jishage K, Yamada H, Sasaguri H, Yokota S, Piao W, Tomimitsu H, Saido TC, Yanagisawa K, Terasaki T, Mizu- sawa H, Yokota T (2009) Depletion of vitamin E increases amyloid beta accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease. J Biol Chem 284, 33400-33408.
45. Hardeland R (2005) Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine 27, 119-130.
46. Larson J, Jessen RE, Uz T, Arslan AD, Kurtuncu M, Imbesi M, Manev H (2006) Impaired hippocampal long-term poten- tiation in melatonin MT2 receptor-deficient mice. Neurosci Lett 393, 23-26.
47. Feng Z, Qin C, Chang Y, Zhang JT (2006) Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer's disease. Free Radic Biol Med 40, 101-109.
48. Olcese JM, Cao C, Mori T, Mamcarz MB, Maxwell A, Run- feldt MJ, Wang L, Zhang C, Lin X, Zhang G, Arendash GW (2009) Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of mela- tonin in a transgenic model of Alzheimer disease. J Pineal Res 47, 82-96.
49. Masilamoni JG, Jesudason EP, Dhandayuthapani S, Ashok BS, Vignesh S, Jebaraj WC, Paul SF, Jayakumar R (2008) The neuroprotective role of melatonin against amyloid beta peptide injected mice. Free Radic Res 42, 661-673.
50. 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.
51. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Am- begaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 280, 5892-5901.
52. Zhang L, Fiala M, Cashman J, Sayre J, Espinosa A, Mahanian M, Zaghi J, Badmaev V, Graves MC, Bernard G, Rosenthal M (2006) Curcuminoids enhance amyloid-beta uptake by macrophages of Alzheimer's disease patients. J Alzheimers Dis 10, 1-7.
53. Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bac- skai BJ (2007) Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem 102, 1095-1104.
54. Joseph JA, Denisova NA, Arendash G, Gordon M, Diamond D, Shukitt-Hale B, Morgan D (2003) Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci 6, 153-162.
55. Ho L, Chen LH, Wang J, Zhao W, Talcott ST, Ono K, Teplow D, Humala N, Cheng A, Percival SS, Ferruzzi M, Janle E, Dickstein DL, Pasinetti GM (2009) Heterogeneity in red wine polyphenolic contents differentially influences Alzheimer's disease-type neuropathology and cognitive deterioration. J Alzheimers Dis 16, 59-72.
56. Ono K, Condron MM, Ho L, Wang J, Zhao W, Pasinetti GM, Teplow DB (2008) Effects ofgrape seed-derived polyphenols on amyloid beta-protein self-assembly and cytotoxicity. J Biol Chem 283, 32176-32187.
57. Wang J, Ho L, Zhao Z, Seror I, Humala N, Dickstein DL, Thiyagarajan M, Percival SS, Talcott ST, Pasinetti GM (2006) Moderate consumption of Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer's disease. FASEBJ 20, 2313-2320.
58. Karuppagounder SS, Pinto JT, Xu H, Chen HL, Beal MF, Gibson GE (2009) Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model ofAlzheimer's disease. Neurochem Int 54, 111-118.
59. Vingtdeux V, Giliberto L, Zhao H, Chandakkar P, Wu Q, Simon JE, Janle EM, Lobo J, Ferruzzi MG, Davies P, Marambaud P AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-{beta} Peptide Metabolism. J Biol Chem 285, 9100-9113.
60. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ (1997) A controlled trial of selegi- line, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl JMed 336, 1216-1222.
61. ShoulsonI (1998) DATATOP: a decade of neuroprotective inquiry. Parkinson Study Group. Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism. Ann Neurol 44, S160- 166.
62. Kieburtz K, McDermott M, Como P, Growdon J, Brady J, Carter J, Huber S, Kanigan B, Landow E, Rudolph A, et al. (1994) The effect of deprenyl and tocopherol on cognitive performance in early untreated Parkinson's disease. Parkinson Study Group. Neurology 44, 1756-1759.
63. Parnetti L, Ambrosoli L, Abate G, Azzini C, Balestreri R, Bartorelli L, Bordin A, Crepaldi G, Cristianini G, Cucinotta D, et al. (1995) Posatirelin for the treatment of late-onset Alzheimer's disease: a double-blind multicentre study vs citicoline and ascorbic acid. Acta Neurol Scand 92, 135-140.
64. Jack CR, Jr., Petersen RC, Grundman M, Jin S, Gamst A, Ward CP, Sencakova D, Doody RS, Thal LJ (2008) Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI. Neurobiol Aging 29, 1285-1295.
65. Vatassery GT, Fahn S, Kuskowski MA (1998) Alpha tocopherol in CSF of subjects taking high-dose vitamin E in the DATATOP study. Parkinson Study Group. Neurology 50, 1900-1902.
66. Gomez-Isla T, Price JL, McKeel DW, Jr., Morris JC, Grow- don JH, Hyman BT (1996) Profound loss of layer II entorhi- nal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci 16, 4491-4500.
67. Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC (2001) Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 58, 1395-1402.
68. Morris MC, Beckett LA, Scherr PA, Hebert LE, Bennett DA, Field TS, Evans DA (1998) Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease. Alzheimer Dis Assoc Disord 12, 121-126.
69. Masaki KH, Losonczy KG, Izmirlian G, Foley DJ, Ross GW, Petrovitch H, Havlik R, White LR (2000) Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 54, 1265-1272.
70. Maxwell CJ, Hicks MS, Hogan DB, Basran J, Ebly EM (2005) Supplemental use of antioxidant vitamins and subsequent risk of cognitive decline and dementia. Dement Geriatr Cogn Disord 20, 45-51.
71. Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JC, Breteler MM (2002) Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 287, 3223-3229.
72. Grodstein F, Chen J, Willett WC (2003) High-dose antiox- idant supplements and cognitive function in community- dwelling elderly women. Am J Clin Nutr 77, 975-984.
73. Zandi PP, Anthony JC, Khachaturian AS, Stone SV, Gustafson D, Tschanz JT, Norton MC, Welsh-Bohmer KA, Breitner JC (2004) Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol 61, 82-88.
74. Wengreen HJ, Munger RG, Corcoran CD, Zandi P, Hayden KM, Fotuhi M, Skoog I, Norton MC, Tschanz J, Breitner JC, Welsh-Bohmer KA (2007) Antioxidant intake and cognitive function of elderly men and women: the Cache County Study. J Nutr Health Aging 11, 230-237.
75. Mendelsohn AB, Belle SH, Stoehr GP, Ganguli M (1998) Use of antioxidant supplements and its association with cognitive function in a rural elderly cohort: the MoVIES Project. Monongahela Valley Independent Elders Survey. Am J Epidemiol 148, 38-44.
76. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Wilson RS, Scherr PA (2002) Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in abiracial community study. JAMA 287, 3230-3237.
77. Luchsinger JA, Tang MX, Shea S, Mayeux R (2003) An- tioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol 60, 203-208.
78. Yaffe K, Clemons TE, McBee WL, Lindblad AS (2004) Impact of antioxidants, zinc, and copper on cognition in the elderly: a randomized, controlled trial. Neurology 63, 17051707.
79. Kang JH, Cook N, Manson J, Buring JE, Grodstein F (2006) A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med 166, 2462-2468.
80. Miller ER, 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142, 37-46.
81. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297, 842-857.
82. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2008) Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database SystRev, CD007176.
83. Bergamasco B, Scarzella L, La Commare P (1994) Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type. Funct Neurol 9, 161-168.
84. Weyer G, Babej-Dolle RM, Hadler D, Hofmann S, Herrmann WM (1997) A controlled study of 2 doses of idebenone in the treatment of Alzheimer's disease. Neuropsychobiology 36, 73-82.
85. Gutzmann H, Hadler D (1998) Sustained efficacy and safety ofidebenone in the treatment ofAlzheimer's disease: update on a 2-year double-blind multicentre study. J Neural Transm Suppl 54, 301-310.
86. Gutzmann H, Kuhl KP, Hadler D, Rapp MA (2002) Safety and efficacy of idebenone versus tacrine in patients with Alzheimer's disease: results of a randomized, double-blind, parallel-group multicenter study. Pharmacopsychiatry 35, 12-18.
87. Thal LJ, Grundman M, Berg J, Ernstrom K, Margolin R, Pfeiffer E, Weiner MF, Zamrini E, Thomas RG (2003) Idebenone treatment fails to slow cognitive decline in Alzheimer's disease. Neurology 61, 1498-1502.
88. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL (2003) Metal- protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol 60, 16851691.
89. Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 7, 779-786.
90. Frautschy SA, Hu W, Kim P, Miller SA, Chu T, Harris-White ME, Cole GM (2001) Phenolic anti-inflammatory antioxi- dant reversal of Abeta-induced cognitive deficits and neu- ropathology. Neurobiol Aging 22, 993-1005.
91. Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, Lam L, Leung V, Hui E, Ng C, Woo J, Chiu HF, Goggins WB, Zee BC, Cheng KF, Fong CY, Wong A, Mok H, Chow MS, Ho PC, Ip SP, Ho CS, Yu XW, Lai CY, Chan MH, Szeto S, Chan IH, Mok V (2008) Six-month randomized, placebo- controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol 28, 110-113.
92. Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D (2008) Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet 372, 207-215.
93. Kieburtz K, McDermott MP, Voss TS, Corey-Bloom J, Deuel LM, Dorsey ER, Factor S, Geschwind MD, Hodgeman K, Kayson E, Noonberg S, Pourfar M, Rabinowitz K, Ravina B, Sanchez-Ramos J, Seely L, Walker F, Feigin A (2010) A randomized, placebo-controlled trial of latrepirdine in Hunt- ington disease. Arch Neurol 67, 154-160.
94. Grigorev VV, Dranyi OA, Bachurin SO (2003) Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med 136, 474-477.
95. Lermontova NN, Redkozubov AE, Shevtsova EF, Serkova TP, Kireeva EG, Bachurin SO (2001) Dimebon and tacrine inhibit neurotoxic action ofbeta-amyloid in culture and block L-type Ca(2+) channels. Bull Exp Biol Med 132, 1079-1083.
96. Bachurin SO, Shevtsova EP, Kireeva EG, Oxenkrug GF, Sablin SO (2003) Mitochondria as a target for neurotoxins and neuroprotective agents. Ann N Y Acad Sci 993, 334-344; discussion 345-1339
97. ClinicalTrials.gov (2009) A safety and efficacy study of oral Dimebon in patients with mild-to-moderate Alzheimer's disease (CONNECTION), http://clinicaltrials.gov/ct2/show/NCT00675623, July 14, 2009, Accessed March 10, 2010.
98. Alzheimer Research Forum (2010) Dimebon disappoints in Phase 3 trial, http://www.alzforum.org/new/detail.asp?id=2387, March 4, 2010, Accessed March 10, 2010.
99. Moi P, Chan K, Asunis I, Cao A, Kan YW (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF- E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA 91, 9926-9930.
100. Li W, Kong AN (2009) Molecular mechanisms of Nrf2- mediated antioxidant response. Mol Carcinog 48, 91-104.
101. Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284, 13291-13295.
102. Kang KW, Lee SJ, Kim SG (2005) Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal 7, 1664-1673.
103. Kanninen K, Malm TM, Jyrkkanen HK, Goldsteins G, Keksa-Goldsteine V, Tanila H, Yamamoto M, Yla-Herttuala S, Levonen AL, Koistinaho J (2008) Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Mol Cell Neurosci 39, 302-313.
104. Kanninen K, Heikkinen R, Malm T, Rolova T, Kuhmonen S, Leinonen H, Yla-Herttuala S, Tanila H, Levonen AL, Koisti- naho M, Koistinaho J (2009) Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 106, 16505-16510.
105. van Muiswinkel FL, Kuiperij HB (2005) The Nrf2-ARE Signalling pathway: promising drug target to combat oxida- tive stress in neurodegenerative disorders. Curr. Drug Targets CNS Neurol Disord 4, 267-281.
106. Liby K, Hock T, Yore MM, Suh N, Place AE, Risingsong R, Williams CR, Royce DB, Honda T, Honda Y, Gribble GW, Hill-Kapturczak N, Agarwal A, Sporn MB (2005) The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res 65, 4789-4798.
107. Liby KT, Yore MM, Sporn MB (2007) Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7, 357-369.
108. Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, Talalay P (2005) Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 102, 4584-4589.
109. Dumont M, Wille E, Calingasan NY, Tampellini D, Williams C, Gouras GK, Liby K, Sporn M, Nathan C, Flint Beal M, Lin MT (2009) Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a trans- genic mouse model of Alzheimer's disease. J Neurochem 109, 502-512.
110. Qin W, Haroutunian V, Katsel P, Cardozo CP, Ho L, Buxbaum JD, Pasinetti GM (2009) PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol 66, 352-361.
111. Rossner S, Sastre M, Bourne K, Lichtenthaler SF (2006) Transcriptional and translational regulation of BACE1 expression - implications for Alzheimer's disease. Prog Neurobiol 79,95-111.
112. Landreth G, Jiang Q, Mandrekar S, Heneka M (2008) PPARgamma agonists as therapeutics for the treatment of Alzheimer's disease. Neurotherapeutics 5, 481-489.
113. Nicolakakis N, Aboulkassim T, Ongali B, Lecrux C, Fer- nandes P, Rosa-Neto P, Tong XK, Hamel E (2008) Complete rescue ofcerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist. J Neurosci 28, 9287-9296.
114. Strum JC, Shehee R, Virley D, Richardson J, Mattie M, Sell- ey P, Ghosh S, Nock C, Saunders A, Roses A (2007) Rosigli- tazone induces mitochondrial biogenesis in mouse brain. J Alzheimers Dis 11, 45-51.
115. Escribano L, Simon AM, Perez-Mediavilla A, Salazar- Colocho P, Del Rio J, Frechilla D (2009) Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model. Biochem Biophys Res Commun 379, 406-410.
116. Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S (2005) Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 13, 950-958.
117. Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD (2006) Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacoge- nomics J 6, 246-254.
118. Hanyu H, Sato T, Kiuchi A, Sakurai H, Iwamoto T (2009) Pioglitazone improved cognition in a pilot study on patients with Alzheimer's disease and mild cognitive impairment with diabetes mellitus. J Am Geriatr Soc 57, 177-179.
119. Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T (2009) Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging, in press.