Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

The Pharmacogenomics Journal volume 6, pages 8–15 (2006)Cite this article

Abstract

Finding an effective treatment for chronic neurodegenerative disorders still represents an unmet goal. There is considerable evidence that such disorders represent a combination of genetic determinants and failure of neuroprotective mechanisms sparking a wider degree of interest in shedding light on the cellular changes responsible for these devastating disorders. Because of their role in survival or differentiation of developing neurons, as well as the recent discovery of their importance in regulating synaptic plasticity during adulthood, neurotrophic factors have been suggested as essential contributors of the etiology of neurodegenerative disorders. Alzheimer's disease (AD) is a complex, chronic, devastating disease that affects a high percentage of the population over 65 years of age. This review will focus on different pharmacological interventions that are currently in use or drugs under development, narrowing the therapeutic agents to those that interfere with the expression of the trophic factor brain-derived neurotrophic factor (BDNF), a molecule playing a pivotal role in synaptic plasticity and cognition. From these findings, it appears clear that BDNF is implicated in the mechanism of action of drugs that improve cognitive deficits in animal models of AD and in AD patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Siegel GJ, Chauhan NB . Neurotrophic factors in Alzheimer's and Parkinson's disease brain. Brain Res Brain Res Rev 2000; 33: 199–227.

    CAS  PubMed  Google Scholar 

  2. Murer MG, Yan Q, Raisman-Vozari R . Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease. Prog Neurobiol 2001; 63: 71–124.

    CAS  PubMed  Google Scholar 

  3. Tuszynski MH, U HS, Amaral DG, Gage FH . Nerve growth factor infusion in the primate brain reduces lesion-induced cholinergic neuronal degeneration. J Neurosci 1990; 10: 3604–3614.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Lu B . BDNF and activity-dependent synaptic modulation. Learn Mem 2003; 10: 86–98.

    PubMed  PubMed Central  Google Scholar 

  5. Mesulam MM . Spatial attention and neglect: parietal, frontal and cingulate contributions to the mental representation and attentional targeting of salient extrapersonal events. Philos Trans R Soc London B 1999; 354: 1325–1346.

    CAS  Google Scholar 

  6. Fahnestock M, Garzon D, Holsinger RM, Michalski B . Neurotrophic factors and Alzheimer's disease: are we focusing on the wrong molecule. J Neural Transm Suppl 2002; 62: 241–252.

    CAS  Google Scholar 

  7. Knipper M, da Penha Berzaghi M, Blochl A, Breer H, Thoenen H, Lindholm D . Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the rat hippocampus. Eur J Neurosci 1994; 6: 668–671.

    CAS  PubMed  Google Scholar 

  8. Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V et al. Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 1999; 24: 401–414.

    CAS  PubMed  Google Scholar 

  9. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW . BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron 1991; 7: 695–702.

    CAS  PubMed  Google Scholar 

  10. Holsinger RM, Schnarr J, Henry P, Castelo VT, Fahnestock M . Quantitation of BDNF mRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer's disease. Brain Res Mol Brain Res 2000; 76: 347–354.

    CAS  PubMed  Google Scholar 

  11. Ferrer I, Marin C, Rey MJ, Ribalta T . Brain-derived neurotrophic factor in patients with frontotemporal dementia. Neurosci Lett 2000; 279: 33–36.

    CAS  PubMed  Google Scholar 

  12. Allen SJ, Wilcock GK, Dawbarn D . Profound and selective loss of catalytic TrkB immunoreactivity in Alzheimer's disease. Biochem Biophys Res Commun 1999; 264: 648–651.

    CAS  PubMed  Google Scholar 

  13. Hock C, Heese K, Hulette C, Rosenberg C, Otten U . Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 2000; 57: 846–851.

    CAS  PubMed  Google Scholar 

  14. Michalski B, Fahnestock M . Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer's disease. Brain Res Mol Brain Res 2003; 111: 148–154.

    CAS  PubMed  Google Scholar 

  15. Murer MG, Boissiere F, Yan Q, Hunot S, Villares J, Faucheux B et al. An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer's disease. Neuroscience 1999; 88: 1015–1032.

    CAS  PubMed  Google Scholar 

  16. Garzon D, Yu G, Fahnestock M . A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer's disease parietal cortex. J Neurochem 2002; 82: 1058–1064.

    CAS  PubMed  Google Scholar 

  17. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.

    Article  CAS  PubMed  Google Scholar 

  18. Kunugi H, Ueki A, Otsuka M, Isse K, Hirasawa H, Kato N . A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol Psychiatry 2001; 6: 83–86.

    CAS  PubMed  Google Scholar 

  19. Ventriglia M, Bocchio Chiavetto L, Benussi L, Binetti G, Zanetti O, Riva MA . Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease. Mol Psychiatry 2002; 7: 136–137.

    CAS  PubMed  Google Scholar 

  20. Nishimura M, Kuno S, Kaji R, Kawakami H . Brain-derived neurotrophic factor gene polymorphisms in Japanese patients with sporadic Alzheimer's disease, Parkinson's disease, and multiple system atrophy. Mov Disord 2005; 20: 1031–1033.

    PubMed  Google Scholar 

  21. Olin D, MacMurray J, Comings DE . Risk of late-onset Alzheimer's disease associated with BDNF C270T polymorphism. Neurosci Lett 2005; 381: 275–278.

    CAS  PubMed  Google Scholar 

  22. Tsai SJ, Hong CJ, Liu HC, Liu TY, Hsu LE, Lin CH . Association analysis of brain-derived neurotrophic factor Val66Met polymorphisms with Alzheimer's disease and age of onset. Neuropsychobiology 2004; 49: 10–12.

    CAS  PubMed  Google Scholar 

  23. Combarros O, Infante J, Llorca J, Berciano J . Polymorphism at codon 66 of the brain-derived neurotrophic factor gene is not associated with sporadic Alzheimer's disease. Dement Geriatr Cogn Disord 2004; 18: 55–58.

    CAS  PubMed  Google Scholar 

  24. Vepsalainen S, Castren E, Helisalmi S, Iivonen S, Mannermaa A, Lehtovirta M . Genetic analysis of BDNF and TrkB gene polymorphisms in Alzheimer's disease. J Neurol 2005; 252: 423–428.

    CAS  PubMed  Google Scholar 

  25. Bodner SM, Berrettini W, van Deerlin V, Bennett DA, Wilson RS, Trojanowski JQ . Genetic variation in the brain derived neurotrophic factor gene in Alzheimer's disease. Am J Med Genet B 2005; 134: 1–5.

    Google Scholar 

  26. Desai P, Nebes R, DeKosky ST, Kamboh MI . Investigation of the effect of brain-derived neurotrophic factor (BDNF) polymorphisms on the risk of late-onset Alzheimer's disease (AD) and quantitative measures of AD progression. Neurosci Lett 2005; 379: 229–234.

    CAS  PubMed  Google Scholar 

  27. Lee J, Fukumoto H, Orne J, Kluchen J, Raju S, Vanderburg CR . Decreased levels of BDNF protein in Alzheimer temporal cortex are independent of BDNF polymorphisms. Exp Neurol 2005; 194: 91–96.

    CAS  PubMed  Google Scholar 

  28. Lemaire V, Koehl M, Le Moal M, Abrous DN . Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci USA 2000; 97: 11032–11037.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Fumagalli F, Bedogni F, Perez J, Racagni G, Riva MA . Corticostriatal brain-derived neurotrophic factor dysregulation in adult rats following prenatal stress. Eur J Neurosci 2004; 20: 1348–1354.

    PubMed  Google Scholar 

  30. Koo JW, Park CH, Choi SH, Kim NJ, Kim HS, Choe JC . The postnatal environment can counteract prenatal effects on cognitive ability, cell proliferation, and synaptic protein expression. FASEB J 2003; 17: 1556–1558.

    CAS  PubMed  Google Scholar 

  31. Betz AL, Goldstein GW, Katzman R . Blood–brain–cerebrospinal fluid barriers. In: Siegel G, Agranoff B, Albers RW, Molinoff P (eds). Basic Neurochemistry. Raven press: New York, 1989, pp 591–606.

    Google Scholar 

  32. Knusel B, Beck KD, Winslow JW, Rosenthal A, Burton LE, Widmer HR . Brain-derived neurotrophic factor administration protects basal forebrain cholinergic but not nigral dopaminergic neurons from degenerative changes after axotomy in the adult rat brain. J Neurosci 1992; 12: 4391–4402.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Lahteinen S, Pitkanen A, Koponen E, Saarelainen T, Castren E . Exacerbated status epilepticus and acute cell loss, but no changes in epileptogenesis, in mice with increased brain-derived neurotrophic factor signaling. Neuroscience 2003; 122: 1081–1092.

    CAS  PubMed  Google Scholar 

  34. Scharfman HE, Goodman JH, Sollas AL, Croll SD . Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. Exp Neurol 2002; 174: 201–214.

    CAS  PubMed  Google Scholar 

  35. Tobias CA, Dhoot NO, Wheatley MA, Tessler A, Murray M, Fischer I . Grafting of encapsulated BDNF-producing fibroblasts into the injured spinal cord without immune suppression in adult rats. J Neurotrauma 2001; 18: 287–301.

    CAS  PubMed  Google Scholar 

  36. Loh NK, Woerly S, Bunt SM, Wilton SD, Harvey AR . The regrowth of axons within tissue defects in the CNS is promoted by implanted hydrogel matrices that contain BDNF and CNTF producing fibroblasts. Exp Neurol 2001; 170: 72–84.

    CAS  PubMed  Google Scholar 

  37. Mitsui T, Fischer I, Shumsky JS, Murray M . Transplants of fibroblasts expressing BDNF and NT-3 promote recovery of bladder and hindlimb function following spinal contusion injury in rats. Exp Neurol 2005; 19: 410–431.

    Google Scholar 

  38. Seo H, Isacson O . Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice. Exp Neurol 2005; 193: 469–480.

    CAS  PubMed  Google Scholar 

  39. Sonkusare SK, Kaul CL, Ramarao P . Dementia of Alzheimer's disease and other neurodegenerative disorders – memantine, a new hope. Pharmacol Res 2005; 5: 1–17.

    Google Scholar 

  40. Schmitt B, Bernhardt T, Moeller HJ, Heuser I, Frolich L . Combination therapy in Alzheimer's disease: a review of current evidence. CNS Drugs 2004; 18: 827–844.

    CAS  PubMed  Google Scholar 

  41. Marvanova M, Lakso M, Pirhonen J, Nawa H, Wong G, Castren E . The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain. Mol Cell Neurosci 2001; 18: 247–258.

    CAS  PubMed  Google Scholar 

  42. Lauterborn JC, Lynch G, Vanderklish P, Arai A, Gall CM . Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J Neurosci 2000; 20: 8–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Legutko B, Li X, Skolnick P . Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator. Neuropharmacology 2001; 40: 1019–1027.

    CAS  PubMed  Google Scholar 

  44. Mackowiak M, O’Neill MJ, Hicks CA, Bleakman D, Skolnick P . An AMPA receptor potentiator modulates hippocampal expression of BDNF: an in vivo study. Neuropharmacology 2002; 43: 1–10.

    CAS  PubMed  Google Scholar 

  45. Lauterborn JC, Truong GS, Baudry M, Bi X, Lynch G, Gall CM . Chronic elevation of brain-derived neurotrophic factor by ampakines. J Pharmacol Exp Ther 2003; 307: 297–305.

    CAS  PubMed  Google Scholar 

  46. Baumbarger PJ, Muhlhauser M, Zhai J, Yang CR, Nisenbaum ES . Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in prefrontal cortical pyramidal neurons by a novel allosteric potentiator. J Pharmacol Exp Ther 2001; 298: 86–102.

    CAS  PubMed  Google Scholar 

  47. Gates M, Ogden A, Bleakman D . Pharmacological effects of AMPA receptor potentiators LY392098 and LY404187 on rat neuronal AMPA receptors in vitro. Neuropharmacology 2001; 40: 984–991.

    CAS  PubMed  Google Scholar 

  48. Lynch G . AMPA receptor modulators as cognitive enhancers. Curr Opin Pharmacol 2004; 4: 4–11.

    CAS  PubMed  Google Scholar 

  49. Ingvar M, Ambros-Ingerson J, Davis M, Granger R, Kessler M, Rogers GA . Enhancement by an ampakine of memory encoding in humans. Exp Neurol 1997; 146: 553–559.

    CAS  PubMed  Google Scholar 

  50. Lynch G, Granger R, Ambros-Ingerson J, Davis CM, Kessler M, Schehr R . Evidence that a positive modulator of AMPA-type glutamate receptors improves delayed recall in aged humans. Exp Neurol 1997; 145: 89–92.

    CAS  PubMed  Google Scholar 

  51. Wise PM . Estrogens and neuroprotection. Trends Endocrinol Metab 2002; 13: 229–230.

    CAS  PubMed  Google Scholar 

  52. Marin R, Guerra B, Hernandez-Jimenez JG, Kang XL, Fraser JD, Lopez FJ . Estradiol prevents amyloid-beta peptide-induced cell death in a cholinergic cell line via modulation of a classical estrogen receptor. Neuroscience 2003; 121: 917–926.

    CAS  PubMed  Google Scholar 

  53. Standridge JB . Pharmacotherapeutic approaches to the prevention of Alzheimer's disease. Am J Geriatr Pharmacother 2004; 2: 119–132.

    CAS  PubMed  Google Scholar 

  54. Levine AJ, Battista M . Estrogen replacement therapy: effects on the cognitive functioning and clinical course of women with Alzheimer's disease. Arch Clin Neuropsychol 2004; 19: 769–778.

    PubMed  Google Scholar 

  55. Brinton RD . Impact of estrogen therapy on Alzheimer's disease: a fork in the road? CNS Drugs 2004; 18: 405–422.

    CAS  PubMed  Google Scholar 

  56. Li R, Shen Y . Estrogen and brain: synthesis, function and diseases. Front Biosci 2005; 10: 257–267.

    CAS  PubMed  Google Scholar 

  57. Bora SH, Liu Z, Kecojevic A, Merchenthaler I, Koliatsos VE . Direct, complex effects of estrogens on basal forebrain cholinergic neurons. Exp Neurol 2005; 194: 506–522.

    CAS  PubMed  Google Scholar 

  58. Sohrabji F, Miranda RC, Toran-Allerand CD . Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor. Proc Natl Acad Sci USA 1995; 9: 11110–11114.

    Google Scholar 

  59. Solum DT, Handa RJ . Estrogen regulates the development of brain-derived neurotrophic factor mRNA and protein in the rat hippocampus. J Neurosci 2002; 22: 2650–2659.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Singh M, Meyer EM, Simpkins JW . The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague–Dawley rats. Endocrinology 1995; 136: 2320–2324.

    CAS  PubMed  Google Scholar 

  61. Gibbs RB . Levels of trkA and BDNF mRNA, but not NGF mRNA, fluctuate across the estrous cycle and increase in response to acute hormone replacement. Brain Res 1998; 23: 787:259–787:268.

    Google Scholar 

  62. Jezierski MK, Sohrabji F . Region- and peptide-specific regulation of the neurotrophins by estrogen. Brain Res Mol Brain Res 2000; 85: 77–84.

    CAS  PubMed  Google Scholar 

  63. Scharfman HE, Maclusky NJ . Similarities between actions of estrogen and BDNF in the hippocampus: coincidence or clue? Trends Neurosci 2005; 28: 79–85.

    CAS  PubMed  Google Scholar 

  64. Hampson AJ, Grimaldi M . Cannabinoid receptor activation and elevated cyclic AMP reduce glutamate neurotoxicity. Eur J Neurosci 2001; 13: 1529–1536.

    CAS  PubMed  Google Scholar 

  65. Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin K, Greenberg DA . Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci 1999; 19: 2987–2995.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos ML . Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 2005; 25: 1904–1913.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA . Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 2004; 89: 134–141.

    CAS  PubMed  Google Scholar 

  68. Butovsky E, Juknat A, Goncharov I, Elbaz J, Eilam R, Zangen A et al. In vivo up-regulation of brain-derived neurotrophic factor in specific brain areas by chronic exposure to Delta-tetrahydrocannabinol. J Neurochem 2005; 93: 802–811.

    CAS  PubMed  Google Scholar 

  69. Froestl W, Gallagher M, Jenkins H, Madrid A, Melcher T, Teichman S . SGS742: the first GABA(B) receptor antagonist in clinical trials. Biochem Pharmacol 2004; 68: 1479–1487.

    CAS  PubMed  Google Scholar 

  70. Helm KA, Haberman RP, Dean SL, Hoyt EC, Melcher T, Lund PK . GABA(B) receptor antagonist SGS742 improves spatial memory and reduces protein binding to the cAMP response element (CRE) in the hippocampus. Neuropharmacology 2005; 48: 956–964.

    CAS  PubMed  Google Scholar 

  71. Nibuya M, Nestler EJ, Duman RS . Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996; 16: 2365–2372.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O . Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest 2004; 114: 1624–1634.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Su Y, Ryder J, Li B, Wu X, Fox N, Solenberg P . Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Biochemistry 2004; 43: 6899–6908.

    CAS  PubMed  Google Scholar 

  74. Phiel CJ, Wilson CA, Lee VM, Klein PS . GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature 2003; 423: 435–439.

    CAS  PubMed  Google Scholar 

  75. De Ferrari GV, Chacon MA, Barria MI, Garrido JL, Godoy JA, Olivares G et al. Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Mol Psychiatry 2003; 8: 195–208.

    CAS  PubMed  Google Scholar 

  76. Alvarez G, Munoz-Montano JR, Satrustegui J, Avila J, Bogonez E, Diaz-Nido J . Regulation of tau phosphorylation and protection against beta-amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer's disease. Bipolar Disord 2002; 4: 153–165.

    CAS  PubMed  Google Scholar 

  77. Wei H, Leeds PR, Qian Y, Wei W, Chen R, Chuang D . Beta-amyloid peptide-induced death of PC 12 cells and cerebellar granule cell neurons is inhibited by long-term lithium treatment. Eur J Pharmacol 2000; 392: 117–123.

    CAS  PubMed  Google Scholar 

  78. Chuang DM . Neuroprotective and neurotrophic actions of the mood stabilizer lithium: can it be used to treat neurodegenerative diseases? Crit Rev Neurobiol 2004; 16: 83–90.

    CAS  PubMed  Google Scholar 

  79. Rowe MK, Chuang DM . Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med 2004; 6: 1–18.

    PubMed  Google Scholar 

  80. Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L . The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 2003; 23: 7311–7316.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Gelinas DS, DaSilva K, Fenili D, St George-Hyslop P, McLaurin J . Immunotherapy for Alzheimer's disease. Proc Natl Acad Sci USA 2004; 101 (Suppl 2): 14657–14662.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO . Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003; 9: 448–452.

    CAS  PubMed  Google Scholar 

  83. Tong L, Balazs R, Thornton PL, Cotman CW . Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. J Neurosci 2004; 28: 24:6799–24:6809.

    Google Scholar 

  84. Faden AI, Knoblach SM, Movsesyan VA, Cernak I . Novel small peptides with neuroprotective and nootropic properties. J Alzheimers Dis 2004; 6 (6 Suppl): S93–S97.

    CAS  PubMed  Google Scholar 

  85. Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM et al. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 2005; 120: 701–713.

    CAS  PubMed  Google Scholar 

  86. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T . APP processing and synaptic function. Neuron 2003; 37: 925–937.

    CAS  PubMed  Google Scholar 

  87. Adlard PA, Perreau VM, Pop V, Cotman CW . Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. J Neurosci 2005; 25: 4217–4221.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH . Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci USA 2001; 98: 3440–3445.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood K . Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol 2001; 58: 498–504.

    CAS  PubMed  Google Scholar 

  90. Luchsinger JA, Mayeux R . Dietary factors and Alzheimer's disease. Lancet Neurol 2004; 3: 579–587.

    PubMed  Google Scholar 

  91. Morris MC, Beckett LA, Scherr PA, Hebert LE, Bennett DA, Field TS . Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease. Alzheimer Dis Assoc Disord 1998; 12: 121–126.

    CAS  PubMed  Google Scholar 

  92. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N . Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 2002; 287: 3230–3237.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  94. Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JC . Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002; 287: 3223–3229.

    CAS  PubMed  Google Scholar 

  95. Markesbery WR, Carney JM . Oxidative alterations in Alzheimer's disease. Brain Pathol 1999; 9: 133–146.

    CAS  PubMed  Google Scholar 

  96. Ickes BR, Pham TM, Sanders LA, Albeck DS, Mohammed AH, Granholm AC . Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Exp Neurol 2000; 164: 45–52.

    CAS  PubMed  Google Scholar 

  97. Vaynman S, Ying Z, Gomez-Pinilla F . Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 2004; 20: 2580–2590.

    PubMed  Google Scholar 

  98. Griesbach GS, Hovda DA, Molteni R, Wu A, Gomez-Pinilla F . Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function. Neuroscience 2004; 125: 129–139.

    CAS  PubMed  Google Scholar 

  99. Wu A, Ying Z, Gomez-Pinilla F . The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci 2004; 19: 1699–1707.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacological Sciences, Center of Neuropharmacology, University of Milan, Milan, Italy

    F Fumagalli, G Racagni & M A Riva

  2. Center of Excellence on Neurodegenerative Diseases (CEND), Milan, Italy

    F Fumagalli, G Racagni & M A Riva

  3. IRCCS San Giovanni di Dio-Fatebenefratelli, Brescia, Italy

    G Racagni

Authors
  1. F Fumagalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Racagni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M A Riva
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to F Fumagalli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fumagalli, F., Racagni, G. & Riva, M. The expanding role of BDNF: a therapeutic target for Alzheimer's disease?. Pharmacogenomics J 6, 8–15 (2006). https://doi.org/10.1038/sj.tpj.6500337

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500337

Keywords

This article is cited by

Search

Advanced search

Quick links