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Neurochemical Research

, Volume 34, Issue 4, pp 670–678 | Cite as

Oxidative Damage and Cognitive Dysfunction: Antioxidant Treatments to Promote Healthy Brain Aging

  • Elizabeth Head
MINI-REVIEW

Abstract

Oxidative damage in the brain may lead to cognitive impairments in aged humans. Further, in age-associated neurodegenerative disease, oxidative damage may be exacerbated and associated with additional neuropathology. Epidemiological studies in humans show both positive and negative effects of the use of antioxidant supplements on healthy cognitive aging and on the risk of developing Alzheimer disease (AD). This contrasts with consistent behavioral improvements in aged rodent models. In a higher mammalian model system that naturally accumulates human-type pathology and cognitive decline (aged dogs), an antioxidant enriched diet leads to rapid learning improvements, memory improvements after prolonged treatment and cognitive maintenance. Cognitive benefits can be further enhanced by the addition of behavioral enrichment. In the brains of aged treated dogs, oxidative damage is reduced and there is some evidence of reduced AD-like neuropathology. In combination, antioxidants may be beneficial for promoting healthy brain aging and reducing the risk of neurodegenerative disease.

Keywords

Acetyl-l-carnitine Alzheimer disease Beagle Beta-amyloid Dog Canine Lipoic acid Oxidative damage 

Notes

Acknowledgement

The canine study was supported by funding from the NIH/NIA AG12694.

References

  1. 1.
    Poon HF, Calabrese V, Scapagnini G, Butterfield DA (2004) Free radicals and brain aging. Clin Geriatr Med 20:329–359PubMedCrossRefGoogle Scholar
  2. 2.
    Liu J, Mori A (1999) Stress, aging, and brain oxidative damage. Neurochem Res 24:1479–1497PubMedCrossRefGoogle Scholar
  3. 3.
    Ames BN, Shigenaga MK (1992) Oxidants are a major contributor to aging. Ann NY Acad Sci 663:85–96PubMedCrossRefGoogle Scholar
  4. 4.
    Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90:7915–7922PubMedCrossRefGoogle Scholar
  5. 5.
    Mori A, Utsumi K, Liu J, Hosokawa M (1998) Oxidative damage in the senescence-accelerated mouse. Ann NY Acad Sci 854:239–250PubMedCrossRefGoogle Scholar
  6. 6.
    Shulman RG, Rothman DL, Behar KL, Hyder F (2004) Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci 27:489–495PubMedCrossRefGoogle Scholar
  7. 7.
    Halliwell B, Gutteridge JMC (1985) Oxygen radicals in the nervous system. Trends Neurosci 8:22–26CrossRefGoogle Scholar
  8. 8.
    Floyd RA, Hensley K (2002) Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging 23:795–807PubMedCrossRefGoogle Scholar
  9. 9.
    Perez-Campo R, Lopez-Torres M, Cadenas S, Rojas C, Barja G (1998) The rate of free radical production as a determinant of the rate of aging: evidence from the comparative approach. J Comp Physiol [B] 168:149–158Google Scholar
  10. 10.
    Liu J, Atamna H, Kuratsune H, Ames BN (2002) Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann NY Acad Sci 959:133–166PubMedGoogle Scholar
  11. 11.
    Nakahara H, Kanno T, Inai Y et al (1998) Mitochondrial dysfunction in the senescence accelerated mouse (SAM). Free Radic Biol Med 24:85–92PubMedCrossRefGoogle Scholar
  12. 12.
    Mecocci P, MacGarvey U et al (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–751PubMedCrossRefGoogle Scholar
  13. 13.
    Wei YH (1998) Oxidative stress and mitochondrial DNA mutations in human aging. Proc Soc Exp Biol Med 217:53–63Google Scholar
  14. 14.
    Shigenaga MK, Hagen TM, Ames BN (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci USA 91:10771–10778PubMedCrossRefGoogle Scholar
  15. 15.
    Hirai K, Aliev G, Nunomura A et al (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023PubMedGoogle Scholar
  16. 16.
    Miquel J, Economos AC, Fleming J, Johnson JE Jr (1980) Mitochondrial role in cell aging. Exp Gerontol 15:575–591PubMedCrossRefGoogle Scholar
  17. 17.
    Wallace DC (1992) Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256:628–632PubMedCrossRefGoogle Scholar
  18. 18.
    Haripriya D, Devi MA, Kokilavani V, Sangeetha P, Panneerselvam C (2004) Age-dependent alterations in mitochondrial enzymes in cortex, striatum and hippocampus of rat brain-potential role of L-Carnitine. Biogerontology 5:355–364PubMedCrossRefGoogle Scholar
  19. 19.
    Crouch PJ, Cimdins K, Duce JA, Bush AI, Trounce IA (2007) Mitochondria in aging and Alzheimer’s disease. Rejuvenation Res 10:349–357PubMedCrossRefGoogle Scholar
  20. 20.
    Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H, Sohal RS (1996) Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proc Natl Acad Sci USA 93:4765–4769PubMedCrossRefGoogle Scholar
  21. 21.
    Liu J (2008) The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res 33:194–203PubMedCrossRefGoogle Scholar
  22. 22.
    Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581PubMedGoogle Scholar
  23. 23.
    Mecocci P, MacGarvey U, Kaufman AE et al (1993) Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol 34:609–616PubMedCrossRefGoogle Scholar
  24. 24.
    Smith CD, Carney JM, Starke-Reed PE et al (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA 88:10540–10543PubMedCrossRefGoogle Scholar
  25. 25.
    Montine TJ, Neely MD, Quinn JF, Beal MF, Markesbery WR, Roberts LJ, Morrow JD (2002) Lipid peroxidation in aging brain and Alzheimer’s disease. Free Radic Biol Med 33:620–626PubMedCrossRefGoogle Scholar
  26. 26.
    Stadtman ER (1992) Protein oxidation and aging. Science 257:1220–1224PubMedCrossRefGoogle Scholar
  27. 27.
    Stadtman ER, Berlett BS (1997) Reactive oxygen-mediated protein oxidation in aging and disease. Chem Res Toxicol 10:485–494PubMedCrossRefGoogle Scholar
  28. 28.
    Berlett BS, Stadtman ER (1997) Protein oxidation in aging, disease, and oxidative stress. JBC 272:20313–20316CrossRefGoogle Scholar
  29. 29.
    Cini M, Moretti A (1995) Studies on lipid peroxidation and protein oxidation in the aging brain. Neurobiol Aging 16:53–57PubMedCrossRefGoogle Scholar
  30. 30.
    Markesbery WR, Lovell MA (1998) Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol Aging 19:33–36PubMedCrossRefGoogle Scholar
  31. 31.
    Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23:134–147PubMedCrossRefGoogle Scholar
  32. 32.
    Pratico D, Delanty N (2000) Oxidative injury in diseases of the central nervous system: focus on Alzheimer’s disease. Am J Med 109:577–585PubMedCrossRefGoogle Scholar
  33. 33.
    Behl C (1999) Alzheimer’s disease and oxidative stress: Implications for novel therapeutic approaches. Prog Neurobiol 57:301–323PubMedCrossRefGoogle Scholar
  34. 34.
    Mirra SS, Heyman A, McKeel D et al (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486PubMedGoogle Scholar
  35. 35.
    Selkoe DJ (1994) Normal and abnormal biology of the beta-amyloid precursor protein. Annu Rev Neurosci 17:489–517PubMedCrossRefGoogle Scholar
  36. 36.
    Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185PubMedCrossRefGoogle Scholar
  37. 37.
    Butterfield DA, Kanski J (2001) Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins. Mech Ageing Dev 122:945–962PubMedCrossRefGoogle Scholar
  38. 38.
    Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17:2653–2657PubMedGoogle Scholar
  39. 39.
    Su JH, Deng G, Cotman CW (1997) Neuronal DNA damage precedes tangle formation and is associated with up-regulation of nitrotyrosine in Alzheimer’s Disease brain. Brain Res 774:193–199PubMedCrossRefGoogle Scholar
  40. 40.
    Hensley K, Hall N, Subramaniam R et al (1995) Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J Neurochem 65:2146–2156PubMedGoogle Scholar
  41. 41.
    Lyras L, Cairns NJ, Jenner A, Jenner P, Halliwell B (1997) An assessment of oxidative damage to proteins, lipids and DNA in brain from patients with Alzheimer’s disease. J Neurochem 68:2061–2069PubMedGoogle Scholar
  42. 42.
    Aksenov MY, Aksenova MV, Butterfield DA, Geddes JW, Markesbery WR (2001) Protein oxidation in the brain in Alzheimer’s disease. Neuroscience 103:373–383PubMedCrossRefGoogle Scholar
  43. 43.
    Castegna A, Aksenov M, Aksenova M et al (2002) Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1. Free Radic Biol Med 33:562–571PubMedCrossRefGoogle Scholar
  44. 44.
    Castegna A, Aksenov M, Thongboonkerd V et al (2002) Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part II: dihydropyrimidinase-related protein 2, alpha-enolase and heat shock cognate 71. J Neurochem 82:1524–1532PubMedCrossRefGoogle Scholar
  45. 45.
    Palmer AM, Burns MA (1994) Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimer’s disease. Brain Res 645:338–342PubMedCrossRefGoogle Scholar
  46. 46.
    Sayre LM, Zelasko DA, Harris PLR, Perry G, Salomon RG, Smith MA (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J Neurochem 68:2092–2097PubMedGoogle Scholar
  47. 47.
    Pratico D, Lee MY, Trojanowski JQ, Rokach J, Fitzgerald GA (1998) Increased F2-isoprostanes in Alzheimer’s disease: evidence for enhanced lipid peroxidation in vivo. FASEB J 12:1777–1783PubMedGoogle Scholar
  48. 48.
    Pratico D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, FitzGerald GA (2000) Increased 8, 12-iso-iPF2alpha-VI in Alzheimer’s disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 48:809–812PubMedCrossRefGoogle Scholar
  49. 49.
    Lovell MA, Markesbery WR (2007) Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer’s disease. Nucleic Acids Res 35:7497–7504PubMedCrossRefGoogle Scholar
  50. 50.
    Lovell MA, Gabbita SP, Markesbery WR (1999) Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF. J Neurochem 72:771–776PubMedCrossRefGoogle Scholar
  51. 51.
    Gabbita SP, Lovell MA, Markesbery WR (1998) Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J Neurochem 71:2034–2040PubMedCrossRefGoogle Scholar
  52. 52.
    Lovell MA, Markesbery WR (2008) Oxidatively modified RNA in mild cognitive impairment. Neurobiol Dis 29:169–175PubMedCrossRefGoogle Scholar
  53. 53.
    Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, Smith MA (1999) RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci 19:1959–1964PubMedGoogle Scholar
  54. 54.
    Pappolla MA, Omar RA, Kim KS, Robakis NK (1992) Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer’s disease. Am J Pathol 140:621–628PubMedGoogle Scholar
  55. 55.
    De Deyn PP, Hiramatsu M, Borggreve F et al (1998) Superoxide dismutase activity in cerebrospinal fluid of patients with dementia and some other neurological disorders. Alzheimer Dis Assoc Disord 12:26–32PubMedCrossRefGoogle Scholar
  56. 56.
    Butterfield DA (2004) Proteomics: a new approach to investigate oxidative stress in Alzheimer’s disease brain. Brain Res 1000:1–7PubMedCrossRefGoogle Scholar
  57. 57.
    Polidori MC, Griffiths HR, Mariani E, Mecocci P (2007) Hallmarks of protein oxidative damage in neurodegenerative diseases: focus on Alzheimer’s disease. Amino Acids 32:553–559PubMedCrossRefGoogle Scholar
  58. 58.
    Cassarino DS, Bennett JP Jr (1999) An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Brain Res Rev 29:1–25PubMedCrossRefGoogle Scholar
  59. 59.
    Ojaimi J, Masters CL, Opeskin K, McKelvie P, Byrne E (1999) Mitochondrial respiratory chain activity in the human brain as a function of age. Mech Ageing Dev 111:39–47PubMedCrossRefGoogle Scholar
  60. 60.
    Yan L-J, Levine RL, Sohal RS (1997) Oxidative damage during aging targets mitochondrial aconitase. Proc Natl Acad Sci USA 94:11168–11172PubMedCrossRefGoogle Scholar
  61. 61.
    Michikawa Y, Mazzucchelli F, Bresolin N, Scarlato G, Attardi G (1999) Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication. Science 286:774–779PubMedCrossRefGoogle Scholar
  62. 62.
    Gibson GE, Sheu KF, Blass JP (1998) Abnormalities of mitochondrial enzymes in Alzheimer disease. J Neural Transm 105:855–870PubMedCrossRefGoogle Scholar
  63. 63.
    Bosetti F, Brizzi F, Barogi S et al (2002) Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease. Neurobiol Aging 23:371–376PubMedCrossRefGoogle Scholar
  64. 64.
    Coskun PE, Beal MF, Wallace DC (2004) Alzheimer’s brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci USA 101:10726–10731PubMedCrossRefGoogle Scholar
  65. 65.
    Valla J, Berndt JD, Gonzalez-Lima F (2001) Energy hypometabolism in posterior cingulate cortex of Alzheimer’s patients: superficial laminar cytochrome oxidase associated with disease duration. J Neurosci 21:4923–4930PubMedGoogle Scholar
  66. 66.
    Liang WS, Reiman EM, Valla J et al (2008) Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci USA 105:4441–4446PubMedCrossRefGoogle Scholar
  67. 67.
    Reddy PH (2006) Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer’s disease. J Neurochem 96:1–13PubMedCrossRefGoogle Scholar
  68. 68.
    Butterfield DA, Reed T, Newman SF, Sultana R (2007) Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment. Free Radic Biol Med 43:658–677PubMedCrossRefGoogle Scholar
  69. 69.
    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 Neurosci 21:4183–4187PubMedGoogle Scholar
  70. 70.
    Frederikse PH, Garland D, Zigler JS Jr, Piatigorsky J (1996) Oxidative stress increases production of beta-amyloid precursor protein and beta-amyloid (Abeta) in mammalian lenses, and Abeta has toxic effects on lens epithelial cells. JBC 271:10169–10174CrossRefGoogle Scholar
  71. 71.
    Tamagno E, Bardini P, Obbili A et al (2002) Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 10:279–288PubMedCrossRefGoogle Scholar
  72. 72.
    Butterfield DA (1997) beta-Amyloid-associated free radical oxidative stress and neurotoxicity: implications for Alzheimer’s disease. Chem Res Toxicol 10:495–506PubMedCrossRefGoogle Scholar
  73. 73.
    McLellan ME, Kajdasz ST, Hyman BT, Bacskai BJ (2003) In vivo imaging of reactive oxygen species specifically associated with thioflavine S-positive amyloid plaques by multiphoton microscopy. J Neurosci 23:2212–2217PubMedGoogle Scholar
  74. 74.
    Hensley K, Carney JM, Mattson MP et al (1994) A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci USA 91:3270–3274PubMedCrossRefGoogle Scholar
  75. 75.
    Kim HS, Lee JH, Lee JP et al (2002) Amyloid beta peptide induces cytochrome C release from isolated mitochondria. NeuroReport 13:1989–1993PubMedCrossRefGoogle Scholar
  76. 76.
    Casley CS, Canevari L, Land JM, Clark JB, Sharpe MA (2002) Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem 80:91–100PubMedCrossRefGoogle Scholar
  77. 77.
    Lustbader JW, Cirilli M, Lin C et al (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 304:448–452PubMedCrossRefGoogle Scholar
  78. 78.
    Hansson CA, Frykman S, Farmery MR et al (2004) Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. J Biol Chem 279:51654–51660PubMedCrossRefGoogle Scholar
  79. 79.
    Yan SD, Yan SF, Chen X et al (1995) Non-enzymatically glycated tau in Alzheimer’s disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat Med 1:693–699PubMedCrossRefGoogle Scholar
  80. 80.
    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 287:3223–3229PubMedCrossRefGoogle Scholar
  81. 81.
    Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS (2002) Vitamin E and cognitive decline in older persons. Arch Neurol 59:1125–1132PubMedCrossRefGoogle Scholar
  82. 82.
    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 20:45–51PubMedCrossRefGoogle Scholar
  83. 83.
    Luchsinger JA, Tang MX, Shea S, Mayeux R (2003) Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol 60:203–208PubMedCrossRefGoogle Scholar
  84. 84.
    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 cogntive function and dementia in elderly men. Neurology 54:1265–1272PubMedGoogle Scholar
  85. 85.
    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 166:2462–2468PubMedCrossRefGoogle Scholar
  86. 86.
    Fillenbaum GG, Kuchibhatla MN, Hanlon JT et al (2005) Dementia and Alzheimer’s disease in community-dwelling elders taking vitamin C and/or vitamin E. Ann Pharmacother 39:2009–2014PubMedCrossRefGoogle Scholar
  87. 87.
    Zandi PP, Anthony JC, Khachaturian AS, Stone SV, Gustafson D, Tschanz JT, Norton C, Welsh-Bohmer KA, Breitner JC, Group CCS (2004) Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the cache county study. Arch Neurol 61:82–88PubMedCrossRefGoogle Scholar
  88. 88.
    Barberger-Gateau P, Raffaitin C, Letenneur L et al (2007) Dietary patterns and risk of dementia: the three-city cohort study. Neurology 69:1921–1930PubMedCrossRefGoogle Scholar
  89. 89.
    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 selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med 336:1216–1222PubMedCrossRefGoogle Scholar
  90. 90.
    Petersen RC, Thomas RG, Grundman M et al (2005) Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 352:2379–2388PubMedCrossRefGoogle Scholar
  91. 91.
    Chandra RK (2001) Effect of vitamin and trace-element supplementation on cognitive function in elderly subjects. Nutrition 17:709–712PubMedCrossRefGoogle Scholar
  92. 92.
    Rai G, Wright G, Scott L, Beston B, Rest J, Exton-Smith AN (1990) Double-blind, placebo controlled study of acetyl-l-carnitine in patients with Alzheimer’s dementia. Curr Med Res Opin 11:638–647PubMedGoogle Scholar
  93. 93.
    Pettegrew JW, Klunk WE, Panchalingam K, Kanfer JN, McClure RJ (1995) Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer’s disease. Neurobiol Aging 16:1–4PubMedCrossRefGoogle Scholar
  94. 94.
    Spagnoli A, Lucca U, Menasce G et al (1991) Long-term acetyl-L-carnitine treatment in Alzheimer’s disease. Neurology 41:1726–1732PubMedGoogle Scholar
  95. 95.
    Bonavita E (1986) Study of the efficacy and tolerability of L-acetylcarnitine therapy in the senile brain. Int J Clin Pharm, Ther & Toxicol 24:511–516Google Scholar
  96. 96.
    Thal LJ, Calvani M, Amato A, Carta A (2000) A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology 55:805–810PubMedGoogle Scholar
  97. 97.
    Brooks JO 3rd, Yesavage JA, Carta A, Bravi D (1998) Acetyl L-carnitine slows decline in younger patients with Alzheimer’s disease: a reanalysis of a double-blind, placebo-controlled study using the trilinear approach. Int Psychogeriatr 10:193–203PubMedCrossRefGoogle Scholar
  98. 98.
    Thal LJ, Carta A, Clarke WR et al (1996) A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer’s disease. Neurology 47:705–711PubMedGoogle Scholar
  99. 99.
    Montgomery SA, Thal LJ, Amrein R (2003) Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol 18:61–71PubMedCrossRefGoogle Scholar
  100. 100.
    Bianchetti A, Rozzini R, Trabucchi M (2003) Effects of acetyl-L-carnitine in Alzheimer’s disease patients unresponsive to acetylcholinesterase inhibitors. Curr Med Res Opin 19:350–353PubMedCrossRefGoogle Scholar
  101. 101.
    Hager K, Marahrens A, Kenklies M, Riederer P, Munch G (2001) Alpha-lipoic acid as a new treatment option for Azheimer type dementia. Arch Gerontol Geriatr 32:275–282PubMedCrossRefGoogle Scholar
  102. 102.
    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):189–193Google Scholar
  103. 103.
    Quinn JF, Bussiere JR, Hammond RS et al (2007) Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol Aging 28:213–225PubMedCrossRefGoogle Scholar
  104. 104.
    Head E, Liu J, Hagen TM et al (2002) Oxidative damage increases with age in a canine model of human brain aging. J Neurochem 82:375–381PubMedCrossRefGoogle Scholar
  105. 105.
    Kiatipattanasakul W, Nakamura S, Kuroki K, Nakayama H, Doi K (1997) Immunohistochemical detection of anti-oxidative stress enzymes in the dog brain. Neuropathology 17:307–312CrossRefGoogle Scholar
  106. 106.
    Skoumalova A, Rofina J, Schwippelova Z, Gruys E, Wilhelm J (2003) The role of free radicals in canine counterpart of senile dementia of the Alzheimer type. Exp Gerontol 38:711–719PubMedCrossRefGoogle Scholar
  107. 107.
    Papaioannou N, Tooten PCJ, van Ederen AM, Bohl JRE, Rofina J, Tsangaris T, Gruys E (2001) Immunohistochemical investigation of the brain of aged dogs. I. Detection of neurofibrillary tangles and of 4-hydroxynonenal protein, an oxidative damage product, in senile plaques. Amyloid 8:11–21PubMedGoogle Scholar
  108. 108.
    Rofina JE, Singh K, Skoumalova-Vesela A et al (2004) Histochemical accumulation of oxidative damage products is associated with Alzheimer-like pathology in the canine. Amyloid 11:90–100PubMedCrossRefGoogle Scholar
  109. 109.
    Opii W, Joshi G, Head E et al (2006) Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: relevance to Alzheimer’s disease. Neurobiol Aging 29(1):51–70Google Scholar
  110. 110.
    Hwang IK, Yoon YS, Yoo KY et al (2008) Differences in lipid peroxidation and Cu, Zn-superoxide dismutase in the hippocampal CA1 region between adult and aged dogs. J Vet Med Sci 70:273–277PubMedCrossRefGoogle Scholar
  111. 111.
    Cummings BJ, Su JH, Cotman CW, White R, Russell MJ (1993) Beta-amyloid accumulation in aged canine brain: a model of plaque formation in Alzheimer’s disease. Neurobiol Aging 14:547–560PubMedCrossRefGoogle Scholar
  112. 112.
    Head E, McCleary R, Hahn FF, Milgram NW, Cotman CW (2000) Region-specific age at onset of beta-amyloid in dogs. Neurobiol Aging 21:89–96PubMedCrossRefGoogle Scholar
  113. 113.
    Hou Y, White RG, Bobik M, Marks JS, Russell MJ (1997) Distribution of beta-amyloid in the canine brain. NeuroReport 8:1009–1012PubMedGoogle Scholar
  114. 114.
    Wisniewski HM, Johnson AB, Raine CS, Kay WJ, Terry RD (1970) Senile plaques and cerebral amyloidosis in aged dogs. Lab Invest 23:287–296PubMedGoogle Scholar
  115. 115.
    Wisniewski HM, Wegiel J, Morys J, Bancher C, Soltysiak Z, Kim KS (1990) Aged dogs: an animal model to study beta-protein amyloidogenesis. In: Maurer K, Riederer P, Beckman H (eds) Alzheimer’s disease epidemiology, neuropathology, neurochemistry and clinics. Springer-Verlag, New York, pp 151–167Google Scholar
  116. 116.
    Selkoe DJ, Schenk D (2003) Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 43:545–584PubMedCrossRefGoogle Scholar
  117. 117.
    Siwak-Tapp CT, Head E, Muggenburg BA, Milgram NW, Cotman CW (2008) Region specific neuron loss in the aged canine hippocampus is reduced by enrichment. Neurobiol Aging 29:521–528CrossRefGoogle Scholar
  118. 118.
    Hwang IK, Lee CH, Li H et al (2008) Comparison of ionized calcium-binding adapter molecule 1 immunoreactivity of the hippocampal dentate gyrus and CA1 region in adult and aged dogs. Neurochem Res 33(7):1309–1315Google Scholar
  119. 119.
    Siwak-Tapp CT, Head E, Muggenburg BA, Milgram NW, Cotman CW (2007) Neurogenesis decreases with age in the canine hippocampus and correlates with cognitive function. Neurobiol Learn Mem 88:249–259PubMedCrossRefGoogle Scholar
  120. 120.
    Su M-Y, Head E, Brooks WM, Wang Z, Muggenberg BA, Adam GE, Sutherland RJ, Cotman CW, Nalcioglu O (1998) MR Imaging of anatomic and vascular characteristics in a canine model of human aging. Neurobiol Aging 19:479–485PubMedCrossRefGoogle Scholar
  121. 121.
    Kimotsuki T, Nagaoka T, Yasuda M, Tamahara S, Matsuki N, Ono K (2005) Changes of magnetic resonance imaging on the brain in beagle dogs with aging. J Vet Med Sci 67:961–967PubMedCrossRefGoogle Scholar
  122. 122.
    Tapp PD, Siwak CT, Gao FQ et al (2004) Frontal lobe volume, function, and beta-amyloid pathology in a canine model of aging. J Neurosci 24:8205–8213PubMedCrossRefGoogle Scholar
  123. 123.
    Milgram NW, Adams B, Callahan H, Head E, Mackay W, Thirlwell C, Cotman CW (1999) Landmark discrimination learning in the dog. Learning & Memory 6:54–61Google Scholar
  124. 124.
    Milgram NW, Head E, Weiner E, Thomas E (1994) Cognitive functions and aging in the dog: acquisition of nonspatial visual tasks. Behav Neurosci 108:57–68PubMedCrossRefGoogle Scholar
  125. 125.
    Chan AD, Nippak PM, Murphey H et al (2002) Visuospatial impairments in aged canines (Canis familiaris): the role of cognitive-behavioral flexibility. Behav Neurosci 116:443–454PubMedCrossRefGoogle Scholar
  126. 126.
    Head E, Mehta R, Hartley J et al (1995) Spatial learning and memory as a function of age in the dog. Behav Neurosci 109:851–858PubMedCrossRefGoogle Scholar
  127. 127.
    Tapp PD, Siwak CT, Estrada J, Holowachuk D, Milgram NW (2003) Effects of age on measures of complex working memory span in the beagle dog (Canis familiaris) using two versions of a spatial list learning paradigm. Learn Mem 10:148–160PubMedCrossRefGoogle Scholar
  128. 128.
    Tapp PD, Siwak CT, Estrada J et al (2003) Size and reversal learning in the beagle dog as a measure of executive function and inhibitory control in aging. Learning & Memory 10:64–73CrossRefGoogle Scholar
  129. 129.
    Studzinski CM, Christie LA, Araujo JA et al (2006) Visuospatial function in the beagle dog: an early marker of cognitive decline in a model of human aging and dementia. Neurobiol Learn Mem 86:197–204PubMedCrossRefGoogle Scholar
  130. 130.
    Head E, Milgram NW, Cotman CW (2001) Neurobiological models of aging in the dog and other vertebrate species. In: Hof P, Mobbs C (eds) Functional neurobiology of aging. Academic Press, San Diego, pp 457–468CrossRefGoogle Scholar
  131. 131.
    Cotman CW, Head E, Muggenburg BA, Zicker S, Milgram NW (2002) Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction. Neurobiol Aging 23:809–818PubMedCrossRefGoogle Scholar
  132. 132.
    Cummings BJ, Head E, Ruehl WW, Milgram NW, Cotman CW (1996) Beta-amyloid accumulation correlates with cognitive dysfunction in the aged canine. Neurobiol Learn Mem 66:11–23PubMedCrossRefGoogle Scholar
  133. 133.
    Head E, Callahan H, Muggenburg BA, Cotman CW, Milgram NW (1998) Visual-discrimination learning ability and beta-amyloid accumulation in the dog. Neurobiol Aging 19:415–425PubMedCrossRefGoogle Scholar
  134. 134.
    Rofina JE, van Ederen AM, Toussaint MJ et al (2006) Cognitive disturbances in old dogs suffering from the canine counterpart of Alzheimer’s disease. Brain Res 1069:216–226PubMedCrossRefGoogle Scholar
  135. 135.
    Pugliese M, Geloso MC, Carrasco JL, Mascort J, Michetti F, Mahy N (2006) Canine cognitive deficit correlates with diffuse plaque maturation and S100beta (−) astrocytosis but not with insulin cerebrospinal fluid level. Acta Neuropathol 111:519–528PubMedCrossRefGoogle Scholar
  136. 136.
    Colle M-A, Hauw J-J, Crespeau F, Uchiara T, Akiyama H, Checler F, Pageat P, Duykaerts C (2000) Vascular and parenchymal Aβ deposition in the aging dog: correlation with behavior. Neurobiol Aging 21:695–704CrossRefGoogle Scholar
  137. 137.
    Milgram NW, Head E, Zicker SC, Ikeda-Douglas CJ, Murphey H, Muggenburg B, Siwak C, Tapp D, Cotman CW (2005) Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study. Neurobiol Aging 26:77–90PubMedCrossRefGoogle Scholar
  138. 138.
    Milgram NW, Head E, Muggenburg BA et al (2002) Landmark discrimination learning in the dog: effects of age, an antioxidant fortified diet, and cognitive strategy. Neurosci Biobehav Rev 26:679–695PubMedCrossRefGoogle Scholar
  139. 139.
    Nippak PM, Mendelson J, Muggenburg B, Milgram NW (2007) Enhanced spatial ability in aged dogs following dietary and behavioural enrichment. Neurobiol Learn Mem 87:610–623PubMedCrossRefGoogle Scholar
  140. 140.
    Siwak CT, Tapp PD, Head E et al (2005) Chronic antioxidant and mitochondrial cofactor administration improves discrimination learning in aged but not young dogs. Prog Neuropsychopharmacol Biol Psychiatry 29:461–469PubMedCrossRefGoogle Scholar
  141. 141.
    Pop V, Head E, Nistor M, Milgram NW, Muggenburg BA, Cotman CW (2003) Reduced Aβ deposition with long-term antioxidant diet treatment in aged canines. Society for Neuroscience, Abstract Viewer/Itinerary Planner, Washington, DCGoogle Scholar
  142. 142.
    Rezai-Zadeh K, Shytle D, Sun N et al (2005) Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 25:8807–8814PubMedCrossRefGoogle Scholar
  143. 143.
    Abdul HM, Butterfield DA (2007) Involvement of PI3 K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. Free Radic Biol Med 42:371–384PubMedCrossRefGoogle Scholar
  144. 144.
    Abdul HM, Calabrese V, Calvani M, Butterfield DA (2006) Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. J Neurosci Res 84:398–408PubMedCrossRefGoogle Scholar
  145. 145.
    Rutten BP, Steinbusch HW, Korr H, Schmitz C (2002) Antioxidants and Alzheimer’s disease: from bench to bedside (and back again). Curr Opin Clin Nutr Metab Care 5:645–651PubMedCrossRefGoogle Scholar
  146. 146.
    Noda Y, Mori A (2007) Antioxidant activities of uyaku (Lindera strychnifolia) leaf extract: a natural extract used in traditional medicine. J Clin Biochem Nutr 41:139–145PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Department of Neurology, Institute for Brain Aging & DementiaUniversity of CaliforniaIrvineUSA

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