Docosahexaenoic Acid and Cognitive Dysfunction

  • Michio HashimotoEmail author
  • Hossain Md Shahdat
  • Masanori Katakura


Docosahexaenoic acid (DHA, C22:6n-3), one of the essential n-3 polyunsaturated fatty acids (n-3 PUFAs) in the brain, exerts a markedly beneficial effect on neuronal cell functions. A reduction in brain DHA content of animals fed n-3 PUFA-deficient diets has been directly linked to the impairment of neuronal development and function of the central nervous system (CNS), mainly of cognitive learning ability. Recent evidence has stressed the potential health benefits of DHA for Alzheimer’s disease (AD) that is characterized by extracellular deposits of amyloid β peptide (Aβ) polymers (as neuritic plaques), intracellular deposits (as neurofibrillary tangles), synaptic loss, and nerve-cell death, which lead to decline in memory-related performance. Notably, elderly people and/or AD patients demonstrate a deficiency of n-3 PUFAs, particularly of DHA. Epidemiological studies have suggested that high intake of fish and/or n-3 PUFAs is inversely associated with cognitive impairment, cognitive decline with aging, and/or AD or the development of dementia such as AD. Dietary administration of DHA significantly protects against and ameliorates the impairment of learning ability in Aβ1–40-infused AD model rats with concurrent increases in the ratio of DHA/arachidonic acid and decreases in the levels of lipid peroxide and reactive oxygen species in cortico-hippocampal tissues. Additionally, dietary DHA significantly reduces the levels of Aβ1–40 peptide in detergent-insoluble membrane fractions isolated from the synaptic membranes of the cortex, indicating that DHA participates in eliminating the amyloid burden from the brains of AD model rats. Studies with the use of a wide variety of methods have revealed that DHA significantly inhibits the in vitro fibrillation of Aβ1–40. Moreover, DHA reduces amyloid fibrillation-induced toxicity in cell cultures. These in vitro data support the in vivo suggestion that DHA ameliorates the cognitive deficits of AD by limiting Aβ polymerization in the brains of AD model rats and demonstrate that consumption of n-3 PUFA DHA may improve cognitive function by preventing and/or delaying age-, vascular dementia- or AD-related cognitive decline. Furthermore, DHA effectively promotes neurogenesis both in vitro and in vivo. This evidence suggests that DHA could be used as one of the target therapeutic agents for eliminating the amyloid burden and promoting neurogenesis in AD.


Multiple Sclerosis Amyloid Fibrillation Newborn Neuron bHLH Transcription Factor Amyloid Burden 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Amyloid β peptide


Alzheimer’s disease


α-linolenic acid


Adenosine triphosphate




Central nervous system


Dentate gyrus


Docosahexaenoic acid


Eicosapentaenoic acid


Glutathione peroxidase


Reduced glutathione


Hairy and enhancer of split 1


Long-term potentiation


Mild cognitive impairment


Multiple sclerosis




Neural stem cell


Peroxisome proliferator-activated receptors


Polyunsaturated fatty acid


Reactive oxygen species


Retinoid X receptor


Sterol regulatory element-binding protein


Thioflavin T


  1. Abad-Rodriguez J, Ledesma MD, Craessaerts K, Perga S, Medina M, Delacourte A, Dingwall C, De Strooper B, Dotti CG. J Cell Biol. 2004; 167:953–60.PubMedCrossRefGoogle Scholar
  2. Arab K, Rossary A, Flourie F, Tourneur Y, Steghens JP. Br J Nutr. 2006; 95:18–26.PubMedCrossRefGoogle Scholar
  3. Bazan NG. Brain Pathol. 2005; 15:159–66.PubMedCrossRefGoogle Scholar
  4. Bjorkhem I, Lutjohann D, Diczfalusy U, Stahle L, Ahlborg G, Wahren J. J Lipid Res. 1998; 39:1594–600.PubMedGoogle Scholar
  5. Bourre JM, Francois M, Youyou A, Dumont O, Piciotti M, Pascal G, Durand G. J Nutr. 1989; 119:1880–92.PubMedGoogle Scholar
  6. Broadhurst CL, Cunnane SC, Crawford MA. Br J Nutr. 1998; 79:3–21.PubMedCrossRefGoogle Scholar
  7. Brunkan AL, Goate AM. J Neurochem. 2005; 93:769–92.PubMedCrossRefGoogle Scholar
  8. Calderon F, Kim HY. J Neurochem. 2004; 90:979–88.PubMedCrossRefGoogle Scholar
  9. Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N, Jr., Ashe KH, Frautschy SA, Cole GM. Neuron. 2004; 43:633–45.PubMedCrossRefGoogle Scholar
  10. Conklin SM, Gianaros PJ, Brown SM, Yao JK, Hariri AR, Manuck SB, Muldoon MF. Neurosci Lett. 2007; 421:209–12.PubMedCrossRefGoogle Scholar
  11. Conquer JA, Tierney MC, Zecevic J, Bettger WJ, Fisher RH. Lipids. 2000; 35:1305–12.PubMedCrossRefGoogle Scholar
  12. Cummings JL, Cole G. JAMA. 2002; 287:2335–8.PubMedCrossRefGoogle Scholar
  13. de la Presa Owens S, Innis SM. J Nutr. 1999; 129:2088–93.PubMedGoogle Scholar
  14. de Wilde MC, Farkas E, Gerrits M, Kiliaan AJ, Luiten PG. Brain Res. 2002; 947:166–73.PubMedCrossRefGoogle Scholar
  15. Delion S, Chalon S, Guilloteau D, Besnard JC, Durand G. J Neurochem. 1996; 66:1582–91.PubMedCrossRefGoogle Scholar
  16. Dyall SC, Michael GJ, Whelpton R, Scott AG, Michael-Titus AT. Neurobiol Aging. 2007; 28:424–39.PubMedCrossRefGoogle Scholar
  17. Farooqui AA, Antony P, Ong WY, Horrocks LA, Freysz L. Brain Res Brain Res Rev. 2004; 45:179–95.PubMedCrossRefGoogle Scholar
  18. Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun H, Faxen-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Arch Neurol. 2006; 63:1402–8.PubMedCrossRefGoogle Scholar
  19. Fujita S, Ikegaya Y, Nishikawa M, Nishiyama N, Matsuki N. Br J Pharmacol. 2001; 132:1417–22.PubMedCrossRefGoogle Scholar
  20. Gallai V, Sarchielli P, Trequattrini A, Franceschini M, Floridi A, Firenze C, Alberti A, Di Benedetto D, Stragliotto E. J Neuroimmunol. 1995; 56:143–53.PubMedCrossRefGoogle Scholar
  21. Gamoh S, Hashimoto M, Sugioka K, Shahdat Hossain M, Hata N, Misawa Y, Masumura S. Neuroscience. 1999; 93:237–41.PubMedCrossRefGoogle Scholar
  22. Gamoh S, Hashimoto M, Hossain S, Masumura S. Clin Exp Pharmacol Physiol. 2001; 28:266–70.PubMedCrossRefGoogle Scholar
  23. Gordon LM, Sauerheber RD, Esgate JA, Dipple I, Marchmont RJ, Houslay MD. J Biol Chem. 1980; 255:4519–27.PubMedGoogle Scholar
  24. Green P, Yavin E. J Neurochem. 1995; 65:2555–60.PubMedCrossRefGoogle Scholar
  25. Hashimoto M, Hossain S, Yamasaki H, Yazawa K, Masumura S. Lipids. 1999; 34:1297–304.PubMedCrossRefGoogle Scholar
  26. Hashimoto M, Hossain MS, Shimada T, Yamasaki H, Fujii Y, Shido O. J Lipid Res. 2001; 42:1160–8.PubMedGoogle Scholar
  27. Hashimoto M, Hossain S, Shimada T, Sugioka K, Yamasaki H, Fujii Y, Ishibashi Y, Oka J, Shido O. J Neurochem. 2002; 81:1084–91.PubMedCrossRefGoogle Scholar
  28. Hashimoto M, Tanabe Y, Fujii Y, Kikuta T, Shibata H, Shido O. J Nutr. 2005; 135:549–55.PubMedGoogle Scholar
  29. Hashimoto M, Hossain S, Shimada T, Shido O. Clin Exp Pharmacol Physiol. 2006a;33:934–9.PubMedCrossRefGoogle Scholar
  30. Hashimoto M, Hossain S, Shido O. Mol Cell Biochem. 2006b;293:1–8.PubMedCrossRefGoogle Scholar
  31. Hashimoto M, Shahdat HM, Yamashita S, Katakura M, Tanabe Y, Fujiwara H, Gamoh S, Miyazawa T, Arai H, Shimada T, Shido O. J Neurochem. 2008; 107:1634–46.PubMedCrossRefGoogle Scholar
  32. Hashimoto M, Hossain S, Tanabe Y, Kawashima A, Harada T, Yano T, Mizuguchi K, Shido O. J Nutr Biochem. 2009; 20:965–73.Google Scholar
  33. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. Pediatrics. 2003; 111: e39–44.CrossRefGoogle Scholar
  34. Holman RT, Johnson SB, Kokmen E. Proc Natl Acad Sci USA. 1989; 86:4720–4.PubMedCrossRefGoogle Scholar
  35. Horrobin DF. Schizophr Res. 1998; 30:193–208.PubMedCrossRefGoogle Scholar
  36. Horrocks LA, Farooqui AA. Prostaglandins Leukot Essent Fatty Acids. 2004; 70:361–72.PubMedCrossRefGoogle Scholar
  37. Hossain MS, Hashimoto M, Masumura S. Neurosci Lett. 1998; 244:157–60.PubMedCrossRefGoogle Scholar
  38. Hossain MS, Hashimoto M, Gamoh S, Masumura S. J Neurochem. 1999; 72:1133–8.PubMedCrossRefGoogle Scholar
  39. Johansson AS, Garlind A, Berglind-Dehlin F, Karlsson G, Edwards K, Gellerfors P, Ekholm-Pettersson F, Palmblad J, Lannfelt L. FEBS J. 2007; 274:990–1000.PubMedCrossRefGoogle Scholar
  40. Jump DB. J Biol Chem. 2002; 277:8755–8.PubMedCrossRefGoogle Scholar
  41. Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R. Exp Cell Res. 2005; 306:343–8.PubMedCrossRefGoogle Scholar
  42. Katakura M, Hashimoto M, Shahdat HM, Gamoh S, Okui T, Matsuzaki K, Shido O. Neuroscience. 2009; 160:651–60.PubMedCrossRefGoogle Scholar
  43. Kawakita E, Hashimoto M, Shido O. Neuroscience. 2006; 139:991–7.PubMedCrossRefGoogle Scholar
  44. Kempermann G, Kuhn HG, Gage FH. Nature. 1997; 386:493–5.PubMedCrossRefGoogle Scholar
  45. Khurana R, Ionescu-Zanetti C, Pope M, Li J, Nielson L, Ramirez-Alvarado M, Regan L, Fink AL, Carter SA. Biophys J. 2003; 85:1135–44.PubMedCrossRefGoogle Scholar
  46. Kitajka K, Puskas LG, Zvara A, Hackler L, Jr., Barcelo-Coblijn G, Yeo YK, Farkas T. Proc Natl Acad Sci USA. 2002; 99:2619–24.PubMedCrossRefGoogle Scholar
  47. Kotani S, Sakaguchi E, Warashina S, Matsukawa N, Ishikura Y, Kiso Y, Sakakibara M, Yoshimoto T, Guo J, Yamashima T. Neurosci Res. 2006; 56:159–64.PubMedCrossRefGoogle Scholar
  48. Lauritzen L, Hansen HS, Jorgensen MH, Michaelsen KF. Prog Lipid Res. 2001; 40:1–94.PubMedCrossRefGoogle Scholar
  49. Le Jeune H, Cecyre D, Rowe W, Meaney MJ, Quirion R. Neuroscience. 1996; 74:349–63.PubMedCrossRefGoogle Scholar
  50. Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N, Jr., Frautschy SA, Cole GM. J Neurosci. 2005; 25:3032–40.PubMedCrossRefGoogle Scholar
  51. Lim S, Suzuki H. J Nutr. 2001; 131:319–24.PubMedGoogle Scholar
  52. Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, Hardy M, Gimenez JM, Chiang N, Serhan CN, Bazan NG. J Biol Chem. 2003; 278:43807–17.PubMedCrossRefGoogle Scholar
  53. Mattson MP. Nature. 2004; 430:631–9.PubMedCrossRefGoogle Scholar
  54. McNamara RK, Carlson SE. Prostaglandins Leukot Essent Fatty Acids. 2006; 75:329–49.PubMedCrossRefGoogle Scholar
  55. Miles EA, Banerjee T, Dooper MM, M’Rabet L, Graus YM, Calder PC. Br J Nutr. 2004; 91:893–903.PubMedCrossRefGoogle Scholar
  56. Moriguchi T, Greiner RS, Salem N, Jr. J Neurochem. 2000; 75:2563–73.PubMedCrossRefGoogle Scholar
  57. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Wilson RS, Aggarwal N, Schneider J. Arch Neurol. 2003; 60:940–6.PubMedCrossRefGoogle Scholar
  58. Murata K, Hattori M, Hirai N, Shinozuka Y, Hirata H, Kageyama R, Sakai T, Minato N. Mol Cell Biol. 2005; 25:4262–71.PubMedCrossRefGoogle Scholar
  59. Neuringer M, Connor WE, Lin DS, Barstad L, Luck S. Proc Natl Acad Sci USA. 1986; 83:4021–5.PubMedCrossRefGoogle Scholar
  60. Nordvik I, Myhr KM, Nyland H, Bjerve KS. Acta Neurol Scand. 2000; 102:143–9.PubMedCrossRefGoogle Scholar
  61. Nourooz-Zadeh J, Liu EH, Yhlen B, Anggard EE, Halliwell B. J Neurochem. 1999; 72:734–40.PubMedCrossRefGoogle Scholar
  62. Oka J, Suzuki E, Goto N, Kameyama T. Neuroreport. 1999; 10:2961–4.PubMedCrossRefGoogle Scholar
  63. Okada M, Amamoto T, Tomonaga M, Kawachi A, Yazawa K, Mine K, Fujiwara M. Neuroscience. 1996; 71:17–25.PubMedCrossRefGoogle Scholar
  64. Phillis JW, Horrocks LA, Farooqui AA. Brain Res Rev. 2006; 52:201–43.PubMedCrossRefGoogle Scholar
  65. Pifferi F, Roux F, Langelier B, Alessandri JM, Vancassel S, Jouin M, Lavialle M, Guesnet P. J Nutr. 2005; 135:2241–6.PubMedGoogle Scholar
  66. Pischon T, Hankinson SE, Hotamisligil GS, Rifai N, Willett WC, Rimm EB. Circulation. 2003;108:155–60.Google Scholar
  67. Rapoport SI, Chang MC, Spector AA. J Lipid Res. 2001; 42:678–85.PubMedGoogle Scholar
  68. Sakamoto T, Cansev M, Wurtman RJ. Brain Res. 2007; 1182:50–9.PubMedCrossRefGoogle Scholar
  69. Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, Tucker KL, Kyle DJ, Wilson PW, Wolf PA. Arch Neurol. 2006; 63:1545–50.PubMedCrossRefGoogle Scholar
  70. Schinder AF, Gage FH. Physiology (Bethesda). 2004; 19:253–61.CrossRefGoogle Scholar
  71. Scott BL, Bazan NG. Proc Natl Acad Sci USA. 1989; 86:2903–7.PubMedCrossRefGoogle Scholar
  72. Shahdat H, Hashimoto M, Shimada T, Shido O. Life Sci. 2004; 74:3009–24.PubMedCrossRefGoogle Scholar
  73. Song H, Stevens CF, Gage FH. Nature. 2002; 417:39–44.PubMedCrossRefGoogle Scholar
  74. Suzuki H, Park SJ, Tamura M, Ando S. Mech Ageing Dev. 1998; 101:119–28.PubMedCrossRefGoogle Scholar
  75. Swank RL, Lerstad O, Strom A, Backer J. N Engl J Med. 1952; 246:722–8.PubMedCrossRefGoogle Scholar
  76. Tanabe Y, Hashimoto M, Sugioka K, Maruyama M, Fujii Y, Hagiwara R, Hara T, Hossain SM, Shido O. Clin Exp Pharmacol Physiol. 2004; 31:700–3.PubMedCrossRefGoogle Scholar
  77. Wainwright PE, Huang YS, Coscina DV, Levesque S, McCutcheon D. Dev Psychobiol. 1994; 27:467–87.PubMedCrossRefGoogle Scholar
  78. Yamamoto N, Saitoh M, Moriuchi A, Nomura M, Okuyama H. J Lipid Res. 1987; 28:144–51.PubMedGoogle Scholar
  79. Yehuda S, Rabinovitz S, Carasso RL, Mostofsky DI. Neurobiol Aging. 2002; 23:843–53.PubMedCrossRefGoogle Scholar
  80. Young C, Gean PW, Chiou LC, Shen YZ. Synapse. 2000; 37:90–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Michio Hashimoto
    • 1
    Email author
  • Hossain Md Shahdat
  • Masanori Katakura
  1. 1.Department of Environmental PhysiologyShimane University Faculty of MedicineIzumoJapan

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