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BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease

Gene Therapy volume 17, pages 1294–1308 (2010)Cite this article

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Abstract

Brain-derived neurotrophic factor (BDNF) is the main candidate for neuroprotective therapeutic strategies for Huntington's disease. However, the administration system and the control over the dosage are still important problems to be solved. Here we generated transgenic mice overexpressing BDNF under the promoter of the glial fibrillary acidic protein (GFAP) (pGFAP-BDNF mice). These mice are viable and have a normal phenotype. However, intrastriatal administration of quinolinate increased the number of reactive astrocytes and enhanced the release of BDNF in pGFAP-BDNF mice compared with wild-type mice. Coincidentally, pGFAP-BDNF mice are more resistant to quinolinate than wild-type mice, suggesting a protective effect of astrocyte-derived BDNF. To verify this, we next cultured astrocytes from pGFAP-BDNF and wild-type mice for grafting. Wild-type and pGFAP-BDNF-derived astrocytes behave similarly in nonlesioned mice. However, pGFAP-BDNF-derived astrocytes showed higher levels of BDNF and larger neuroprotective effects than the wild-type ones when quinolinate was injected 30 days after grafting. Interestingly, mice grafted with pGFAP-BDNF astrocytes showed important and sustained behavioral improvements over time after quinolinate administration as compared with mice grafted with wild-type astrocytes. These findings show that astrocytes engineered to release BDNF can constitute a therapeutic approach for Huntington's disease.

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Acknowledgements

We thank MT Muñoz and A López for the technical support. This work was supported by grants from the Ministerio de Educación y Ciencia (SAF2008-04360, JA; SAF2006-04202, JMC), CIBERNED and Red de Terapia Celular (RD06 0010/0006) Fondo de Investigaciones Sanitarias (Instituto de Salud Carlos III), Fundació la Marató de TV3 and High Q Fundation. Mice were generated with support from a grant to Garth M Bray and Albert J Aguayo from the MS Society of Canada. The GFAP promoter sequence was obtained from J Henderson. BDNF c-myc cDNAs were kindly provided by Y Barde. We also thank Dr M Okabe (Research Institute for Microbial Diseases, Osaka University, Japan) for the kind donation of mice transgenic for mutant enhanced green fluorescent protein.

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Authors and Affiliations

  1. Facultat de Medicina, Departament de Biologia Cel·lular, Immunologia i Neurociències, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain

    A Giralt, B Caneda-Ferrón, N Urbán, E Moreno, J M Canals & J Alberch

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Barcelona, Spain

    A Giralt, B Caneda-Ferrón, N Urbán, E Moreno, J M Canals & J Alberch

  3. Laboratory of Developmental Biology, Molecular Oncology Group, McGill University Health Centre, Montreal, Quebec, Canada

    H C Friedman & A Peterson

  4. Cardiovascular Research Center (CSIC-ICCC) Barcelona and Centro de Investigación Biomédica en Red sobre Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain

    N Rubio & J Blanco

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  1. A Giralt
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Correspondence to J Alberch.

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Giralt, A., Friedman, H., Caneda-Ferrón, B. et al. BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease. Gene Ther 17, 1294–1308 (2010). https://doi.org/10.1038/gt.2010.71

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