title: BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease.
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.
authors.affiliation: Facultat de Medicina, Departament de Biologia Cel·lular, Immunologia i Neurociències, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Giralt
authors.forename: H C
authors.initials: HC
authors.lastname: Friedman
authors.forename: B
authors.initials: B
authors.lastname: Caneda-Ferrón
authors.forename: N
authors.initials: N
authors.lastname: Urbán
authors.forename: E
authors.initials: E
authors.lastname: Moreno
authors.forename: N
authors.initials: N
authors.lastname: Rubio
authors.forename: J
authors.initials: J
authors.lastname: Blanco
authors.forename: A
authors.initials: A
authors.lastname: Peterson
authors.forename: J M
authors.initials: JM
authors.lastname: Canals
authors.forename: J
authors.initials: J
authors.lastname: Alberch
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics* / Q000378:metabolism; D006816:Huntington Disease / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017378:Quinolinic Acid / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D017378:Quinolinic Acid