Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Albert Giralt,Jordi Alberch,Eduardo D Martín,Cristina Lao-Peregrin,Olga Carretón

doi:10.1186/1750-1326-6-71

Abstract

BackgroundBrain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems.ResultsHere we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions. In these R6/2:pGFAP-BDNF animals, the decrease in striatal BDNF levels induced by mutant huntingtin was prevented in comparison to R6/2 animals at 12 weeks of age. The recovery of the neurotrophin levels in R6/2:pGFAP-BDNF mice correlated with an improvement in several motor coordination tasks and with a significant delay in anxiety and clasping alterations. Therefore, we next examined a possible improvement in cortico-striatal connectivity in R62:pGFAP-BDNF mice. Interestingly, we found that the over-expression of BDNF prevented the decrease of cortico-striatal presynaptic (VGLUT1) and postsynaptic (PSD-95) markers in the R6/2:pGFAP-BDNF striatum. Electrophysiological studies also showed that basal synaptic transmission and synaptic fatigue both improved in R6/2:pGAP-BDNF mice.ConclusionsThese results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity.

Highlights

Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington’s disease (HD), but its conditional administration is one of its most challenging problems
We previously demonstrated in an excitotoxic model of HD that transgenic astrocytes engineered to overexpress BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter, when grafted in wt mice, release higher levels of BDNF than control astrocytes [23]
As previously observed in the excitotoxic model [23], this neuropathological hallmark induced an up-regulation of the pGFAP-BDNF transgene activity only in R6/2:pGFAP-BDNF mice, which correlates with significantly higher striatal BDNF levels than in R6/2 mice (Figure 1C)

Summary

Introduction

Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington’s disease (HD), but its conditional administration is one of its most challenging problems. Mutant htt (mhtt) causes cortical atrophy and the preferential death of medium-sized spiny neurons in the striatum. The demise of these neurons causes motor and cognitive dysfunction [3]. Brain-Derived Neurotrophic Factor (BDNF) is an important neuroprotective factor for the preservation of medium-sized spiny neurons in the striatum [6]. As one pathogenic mechanism leading to dysfunction and loss of striatal neurons in HD might be the reduction in BDNF levels, its administration should improve these alterations [20,21,22]. The main challenge is to find the way to administer BDNF chronically and conditionally to the target neurons [22,26,27,28]

Methods

Results

Conclusion