Cellular and Molecular Neurobiology

, Volume 31, Issue 8, pp 1229–1243 | Cite as

Adenoviral Astrocyte-Specific Expression of BDNF in the Striata of Mice Transgenic for Huntington’s Disease Delays the Onset of the Motor Phenotype

  • Leticia Arregui
  • Jorge A. Benítez
  • Luis F. Razgado
  • Paula Vergara
  • Jose SegoviaEmail author
Original Research


Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. The most characteristic structural feature of this disease is neurodegeneration accompanied by gliosis in the striatum. BDNF has been proposed to protect striatal neurons from degeneration, because it is an important survival factor for these neurons from development to adulthood. Considering the extensive gliosis and the survival effects of BDNF, we constructed an adenovirus to express a BDNF cDNA in astrocyte cells using a promoter of the glial fibrillary acidic protein gene. Cells stably transfected in vitro with a BDNF cDNA driven by this promoter expressed BDNF and responded to external stimuli increasing BDNF production. When the vector was applied into the striata of mice transgenic for HD, long-term expression of the transgene was observed, associated with a delay of onset of the motor phenotype of the R6/2 HD transgenic mice. The present data indicate that the striatal expression of BDNF is a potential adjuvant for the treatment of HD.


Brain-derived neurotrophic factor Huntington’s disease Glial fibrillary acidic protein promoter Adenovirus Gene therapy 



We want to thank Dr. M. Mouradian for the kind gift of the BDNF cDNA, Dr. B. Vogelstein (Johns Hopkins University) for providing us with the reagents (pAdSystem) to construct the adenoviral vectors, and Dr. M. Hernández (Cinvestav) for providing us with the antibody against β-actin. We thank R. Sánchez for technical support. This work was partially supported by Conacyt Grants 42721-M and 54756 (JS).


  1. Abiru Y, Katoh-Semba R, Nishio C, Hatanaka H (1998) High potassium enhances secretion of neurotrophic factors from cultured astrocytes. Brain Res 809:115–126PubMedCrossRefGoogle Scholar
  2. Altar CA, Cai N, Bliven T, Juhasz M, Conner JM, Acheson AL, Lindsay RM, Wiegand SJ (1997) Anterograde transport of brain-derived neurotrophic factor and its role in the brain. Nature 389:856–860PubMedCrossRefGoogle Scholar
  3. Apostol BL, Simmons DA, Zuccato C, Illes K, Pallos J, Casale M, Conforti P, Ramos C, Roarke M, Kathuria S, Cattaneo E, Marsh JL, Thompson LM (2008) CEP-1347 reduces mutant huntingtin-associated neurotoxicity and restores BDNF levels in R6/2 mice. Mol Cell Neurosci 39:8–20PubMedCrossRefGoogle Scholar
  4. Arregui L, Segovia J (2009) Transgenic murine models for Huntington’s disease. In: Lilia Rocha-Arrieta L, Granados-Soto V (eds) Models of neuropharmacology. Research Signpost, Kerala, pp 35–60Google Scholar
  5. Baquet ZC, Gorski JA, Jones KR (2004) Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor. J Neurosci 24:4250–4258PubMedCrossRefGoogle Scholar
  6. Bemelmans AP, Horellou P, Pradier L, Brunet I, Colin P, Mallet J (1999) Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington’s disease, as demonstrated by adenoviral gene transfer. Hum Gene Ther 10:2987–2997PubMedCrossRefGoogle Scholar
  7. Benitez JA, Segovia J (2003) Gene therapy targeting in the central nervous system. Curr Gene Ther 3:127–145PubMedCrossRefGoogle Scholar
  8. Benitez JA, Arregui L, Vergara P, Segovia J (2007) Targeted-simultaneous expression of Gas1 and p53 using a bicistronic adenoviral vector in gliomas. Cancer Gene Ther 14:836–846PubMedCrossRefGoogle Scholar
  9. Bergami M, Santi S, Formaggio E, Cagnoli C, Verderio C, Blum R, Berninger B, Matteoli M, Canossa M (2008) Uptake and recycling of pro-BDNF for transmitter-induced secretion by cortical astrocytes. J Cell Biol 183:213–221PubMedCrossRefGoogle Scholar
  10. Bogush A, Pedrini S, Pelta-Heller J, Chan T, Yang Q, Mao Z, Sluzas E, Gieringer T, Ehrlich ME (2007) AKT and CDK5/p35 mediate brain-derived neurotrophic factor induction of DARPP-32 in medium size spiny neurons in vitro. J Biol Chem 282:7352–7359PubMedCrossRefGoogle Scholar
  11. Brenner M, Kisseberth WC, Su Y, Besnard F, Messing A (1994) GFAP promoter directs astrocyte-specific expression in transgenic mice. J Neurosci 14:1030–1037PubMedGoogle Scholar
  12. Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, Mori T, Gotz M (2008) Origin and progeny of reactive gliosis: a source of multipotent cells in the injured brain. Proc Natl Acad Sci USA 105:3581–3586PubMedCrossRefGoogle Scholar
  13. Canals JM, Pineda JR, Torres-Peraza JF, Bosch M, Martin-Ibanez R, Munoz MT, Mengod G, Ernfors P, Alberch J (2004) Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease. J Neurosci 24:7727–7739PubMedCrossRefGoogle Scholar
  14. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309PubMedCrossRefGoogle Scholar
  15. Cho SR, Benraiss A, Chmielnicki E, Samdani A, Economides A, Goldman SA (2007) Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. J Clin Invest 117:2889–2902PubMedCrossRefGoogle Scholar
  16. Choi-Lundberg DL, Bohn MC (1995) Ontogeny and distribution of glial cell line-derived neurotrophic factor (GDNF) mRNA in rat. Brain Res Dev Brain Res 85:80–88PubMedCrossRefGoogle Scholar
  17. Chopra V, Fox JH, Lieberman G, Dorsey K, Matson W, Waldmeier P, Housman DE, Kazantsev A, Young AB, Hersch S (2007) A small-molecule therapeutic lead for Huntington’s disease: preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse. Proc Natl Acad Sci USA 104:16685–16689PubMedCrossRefGoogle Scholar
  18. Cicchetti F, Saporta S, Hauser RA, Parent M, Saint-Pierre M, Sanberg PR, Li XJ, Parker JR, Chu Y, Mufson EJ, Kordower JH, Freeman TB (2009) Neural transplants in patients with Huntington’s disease undergo disease-like neuronal degeneration. Proc Natl Acad Sci USA 106:12483–12488PubMedCrossRefGoogle Scholar
  19. Colin E, Regulier E, Perrin V, Durr A, Brice A, Aebischer P, Deglon N, Humbert S, Saudou F (2005) Akt is altered in an animal model of Huntington’s disease and in patients. Eur J Neurosci 21:1478–1488PubMedCrossRefGoogle Scholar
  20. Cortez N, Trejo F, Vergara P, Segovia J (2000) Primary astrocytes retrovirally transduced with a tyrosine hydroxylase transgene driven by a glial-specific promoter elicit behavioral recovery in experimental parkinsonism. J Neurosci Res 59:39–46PubMedCrossRefGoogle Scholar
  21. Cunha C, Angelucci A, D’Antoni A, Dobrossy MD, Dunnett SB, Berardi N, Brambilla R (2009) Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiol Dis 33:358–368PubMedCrossRefGoogle Scholar
  22. Curtis MA, Penney EB, Pearson AG, Roon-Mom WM, Butterworth NJ, Dragunow M, Connor B, Faull RL (2003) Increased cell proliferation and neurogenesis in the adult human Huntington’s disease brain. Proc Natl Acad Sci USA 100:9023–9027PubMedCrossRefGoogle Scholar
  23. Denovan-Wright EM, Attis M, Rodriguez-Lebron E, Mandel RJ (2008) Sustained striatal ciliary neurotrophic factor expression negatively affects behavior and gene expression in normal and R6/1 mice. J Neurosci Res 86:1748–1757PubMedCrossRefGoogle Scholar
  24. Dey ND, Bombard MC, Roland BP, Davidson S, Lu M, Rossignol J, Sandstrom MI, Skeel RL, Lescaudron L, Dunbar GL (2010) Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease. Behav Brain Res 214:193–200PubMedCrossRefGoogle Scholar
  25. Ferrer I, Goutan E, Marin C, Rey MJ, Ribalta T (2000) Brain-derived neurotrophic factor in Huntington disease. Brain Res 866:257–261PubMedCrossRefGoogle Scholar
  26. Galvao RP, Garcia-Verdugo JM, Alvarez-Buylla A (2008) Brain-derived neurotrophic factor signaling does not stimulate subventricular zone neurogenesis in adult mice and rats. J Neurosci 28:13368–13383PubMedCrossRefGoogle Scholar
  27. Garcia-Tovar CG, Perez A, Luna J, Mena R, Osorio B, Aleman V, Mondragon R, Mornet D, Rendon A, Hernandez JM (2001) Biochemical and histochemical analysis of 71 kDa dystrophin isoform (Dp71f) in rat brain. Acta Histochem 103:209–224PubMedCrossRefGoogle Scholar
  28. Gharami K, Xie Y, An JJ, Tonegawa S, Xu B (2008) Brain-derived neurotrophic factor over-expression in the forebrain ameliorates Huntington’s disease phenotypes in mice. J Neurochem 105:369–379PubMedCrossRefGoogle Scholar
  29. Giralt A, Friedman HC, Caneda-Ferron B, Urban N, Moreno E, Rubio N, Blanco J, Peterson A, Canals JM, Alberch J (2010) BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington’s disease. Gene Ther 17:1294–1308PubMedCrossRefGoogle Scholar
  30. Gratacos E, Perez-Navarro E, Tolosa E, Arenas E, Alberch J (2001) Neuroprotection of striatal neurons against kainate excitotoxicity by neurotrophins and GDNF family members. J Neurochem 78:1287–1296PubMedCrossRefGoogle Scholar
  31. Graveland GA, Williams RS, DiFiglia M (1985) Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science 227:770–773PubMedCrossRefGoogle Scholar
  32. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B (1998) A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 95:2509–2514PubMedCrossRefGoogle Scholar
  33. Hickey MA, Gallant K, Gross GG, Levine MS, Chesselet MF (2005) Early behavioral deficits in R6/2 mice suitable for use in preclinical drug testing. Neurobiol Dis 20:1–11PubMedCrossRefGoogle Scholar
  34. Hockly E, Woodman B, Mahal A, Lewis CM, Bates G (2003) Standardization and statistical approaches to therapeutic trials in the R6/2 mouse. Brain Res Bull 61:469–479PubMedCrossRefGoogle Scholar
  35. Ivkovic S, Ehrlich ME (1999) Expression of the striatal DARPP-32/ARPP-21 phenotype in GABAergic neurons requires neurotrophins in vivo and in vitro. J Neurosci 19:5409–5419PubMedGoogle Scholar
  36. Ji Y, Lu Y, Yang F, Shen W, Tang TT, Feng L, Duan S, Lu B (2010) Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 13:302–309PubMedCrossRefGoogle Scholar
  37. Kells AP, Fong DM, Dragunow M, During MJ, Young D, Connor B (2004) AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease. Mol Ther 9:682–688PubMedCrossRefGoogle Scholar
  38. Kordower JH, Chen EY, Winkler C, Fricker R, Charles V, Messing A, Mufson EJ, Wong SC, Rosenstein JM, Bjorklund A, Emerich DF, Hammang J, Carpenter MK (1997) Grafts of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice: trophic and tropic effects in a rodent model of Huntington’s disease. J Comp Neurol 387:96–113PubMedCrossRefGoogle Scholar
  39. Levy YS, Gilgun-Sherki Y, Melamed E, Offen D (2005) Therapeutic potential of neurotrophic factors in neurodegenerative diseases. BioDrugs 19:97–127PubMedCrossRefGoogle Scholar
  40. Lievens JC, Iche M, Laval M, Faivre-Sarrailh C, Birman S (2008) AKT-sensitive or insensitive pathways of toxicity in glial cells and neurons in Drosophila models of Huntington’s disease. Hum Mol Genet 17:882–894PubMedCrossRefGoogle Scholar
  41. Lim ST, Airavaara M, Harvey BK (2010) Viral vectors for neurotrophic factor delivery: a gene therapy approach for neurodegenerative diseases of the CNS. Pharmacol Res 61:14–26PubMedCrossRefGoogle Scholar
  42. Lynch G, Kramar EA, Rex CS, Jia Y, Chappas D, Gall CM, Simmons DA (2007) Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington’s disease. J Neurosci 27:4424–4434PubMedCrossRefGoogle Scholar
  43. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506PubMedCrossRefGoogle Scholar
  44. Miller BR, Dorner JL, Shou M, Sari Y, Barton SJ, Sengelaub DR, Kennedy RT, Rebec GV (2008) Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington’s disease phenotype in the R6/2 mouse. Neuroscience 153:329–337PubMedCrossRefGoogle Scholar
  45. Mizuno K, Carnahan J, Nawa H (1994) Brain-derived neurotrophic factor promotes differentiation of striatal GABAergic neurons. Dev Biol 165:243–256PubMedCrossRefGoogle Scholar
  46. Mowla SJ, Farhadi HF, Pareek S, Atwal JK, Morris SJ, Seidah NG, Murphy RA (2001) Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem 276:12660–12666PubMedCrossRefGoogle Scholar
  47. Nakao N, Kokaia Z, Odin P, Lindvall O (1995) Protective effects of BDNF and NT-3 but not PDGF against hypoglycemic injury to cultured striatal neurons. Exp Neurol 131:1–10PubMedCrossRefGoogle Scholar
  48. Pallier PN, Drew CJ, Morton AJ (2009) The detection and measurement of locomotor deficits in a transgenic mouse model of Huntington’s disease are task- and protocol-dependent: influence of non-motor factors on locomotor function. Brain Res Bull 78:347–355PubMedCrossRefGoogle Scholar
  49. Perez-Severiano F, Rios C, Segovia J (2000) Striatal oxidative damage parallels the expression of a neurological phenotype in mice transgenic for the mutation of Huntington’s disease. Brain Res 862:234–237PubMedCrossRefGoogle Scholar
  50. Pineda JR, Canals JM, Bosch M, Adell A, Mengod G, Artigas F, Ernfors P, Alberch J (2005) Brain-derived neurotrophic factor modulates dopaminergic deficits in a transgenic mouse model of Huntington’s disease. J Neurochem 93:1057–1068PubMedCrossRefGoogle Scholar
  51. Prodoehl J, Corcos DM, Vaillancourt DE (2009) Basal ganglia mechanisms underlying precision grip force control. Neurosci Biobehav Rev 33:900–908PubMedCrossRefGoogle Scholar
  52. Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB (1988) Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci USA 85:5733–5737PubMedCrossRefGoogle Scholar
  53. Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95:55–66PubMedCrossRefGoogle Scholar
  54. Segovia J, Arregui L (2007) Mechanisms of neuronal death associated to Huntington’s disease. In: Massieu L, Arias C, Moran J (eds) The neurochemistry of neuronal death. Research Signpost, Kerala, pp 197–222Google Scholar
  55. Segovia J, Lawless GM, Tillakaratne NJ, Brenner M, Tobin AJ (1994) Cyclic AMP decreases the expression of a neuronal marker (GAD67) and increases the expression of an astroglial marker (GFAP) in C6 cells. J Neurochem 63:1218–1225PubMedCrossRefGoogle Scholar
  56. Segovia J, Vergara P, Brenner M (1998) Differentiation-dependent expression of transgenes in engineered astrocyte cell lines. Neurosci Lett 242:172–176PubMedCrossRefGoogle Scholar
  57. Selkoe DJ, Salazar FJ, Abraham C, Kosik KS (1982) Huntington’s disease: changes in striatal proteins reflect astrocytic gliosis. Brain Res 245:117–125PubMedCrossRefGoogle Scholar
  58. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35PubMedCrossRefGoogle Scholar
  59. Spires TL, Grote HE, Varshney NK, Cordery PM, van Dellen A, Blakemore C, Hannan AJ (2004) Environmental enrichment rescues protein deficits in a mouse model of Huntington’s disease, indicating a possible disease mechanism. J Neurosci 24:2270–2276PubMedCrossRefGoogle Scholar
  60. Steele AD, Jackson WS, King OD, Lindquist S (2007) The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington’s and prion diseases. Proc Natl Acad Sci USA 104:1983–1988PubMedCrossRefGoogle Scholar
  61. Strand AD, Baquet ZC, Aragaki AK, Holmans P, Yang L, Cleren C, Beal MF, Jones L, Kooperberg C, Olson JM, Jones KR (2007) Expression profiling of Huntington’s disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration. J Neurosci 27:11758–11768PubMedCrossRefGoogle Scholar
  62. The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983CrossRefGoogle Scholar
  63. Trejo F, Vergara P, Brenner M, Segovia J (1999) Gene therapy in a rodent model of Parkinson’s disease using differentiated C6 cells expressing a GFAP-tyrosine hydroxylase transgene. Life Sci 65:483–491PubMedCrossRefGoogle Scholar
  64. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577PubMedCrossRefGoogle Scholar
  65. Wang CY, Wang S (2006) Astrocytic expression of transgene in the rat brain mediated by baculovirus vectors containing an astrocyte-specific promoter. Gene Ther 13:1447–1456PubMedCrossRefGoogle Scholar
  66. Xie Y, Hayden MR, Xu B (2010) BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J Neurosci 30:14708–14718PubMedCrossRefGoogle Scholar
  67. Zuccato C, Cattaneo E (2007) Role of brain-derived neurotrophic factor in Huntington’s disease. Prog Neurobiol 81:294–330PubMedCrossRefGoogle Scholar
  68. Zuccato C, Marullo M, Conforti P, MacDonald ME, Tartari M, Cattaneo E (2008) Systematic assessment of BDNF and its receptor levels in human cortices affected by Huntington’s disease. Brain Pathol 18:225–238PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Leticia Arregui
    • 1
    • 2
  • Jorge A. Benítez
    • 1
    • 3
  • Luis F. Razgado
    • 1
  • Paula Vergara
    • 1
  • Jose Segovia
    • 1
    Email author
  1. 1.Departamento de Fisiología, Biofísica y NeurocienciasCentro de Investigación y de Estudios Avanzados del IPNMexicoMexico
  2. 2.Departamento de Ciencias Naturales, DCNIUniversidad Autónoma Metropolitana CuajimalpaMexicoMexico
  3. 3.Ludwig Institute for Cancer ResearchUniversity of CaliforniaSan DiegoUSA

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