Molecular Neurobiology

, Volume 49, Issue 3, pp 1126–1142 | Cite as

IGF-1 Intranasal Administration Rescues Huntington's Disease Phenotypes in YAC128 Mice

  • Carla Lopes
  • Márcio Ribeiro
  • Ana I. Duarte
  • Sandrine Humbert
  • Frederic Saudou
  • Luís Pereira de Almeida
  • Michael Hayden
  • A. Cristina Rego
Article

Abstract

Huntington's disease (HD) is an autosomal dominant disease caused by an expansion of CAG repeats in the gene encoding for huntingtin. Brain metabolic dysfunction and altered Akt signaling pathways have been associated with disease progression. Nevertheless, conflicting results persist regarding the role of insulin-like growth factor-1 (IGF-1)/Akt pathway in HD. While high plasma levels of IGF-1 correlated with cognitive decline in HD patients, other data showed protective effects of IGF-1 in HD striatal neurons and R6/2 mice. Thus, in the present study, we investigated motor phenotype, peripheral and central metabolic profile, and striatal and cortical signaling pathways in YAC128 mice subjected to intranasal administration of recombinant human IGF-1 (rhIGF-1) for 2 weeks, in order to promote IGF-1 delivery to the brain. We show that IGF-1 supplementation enhances IGF-1 cortical levels and improves motor activity and both peripheral and central metabolic abnormalities in YAC128 mice. Moreover, decreased Akt activation in HD mice brain was ameliorated following IGF-1 administration. Upregulation of Akt following rhIGF-1 treatment occurred concomitantly with increased phosphorylation of mutant huntingtin on Ser421. These data suggest that intranasal administration of rhIGF-1 ameliorates HD-associated glucose metabolic brain abnormalities and mice phenotype.

Keywords

Huntington's disease IGF-1 YAC128 mice Huntingtin phosphorylation Energy metabolism Signaling pathways Animal behavior 

Notes

Acknowledgments

This work was supported by “Fundação para a Ciência e a Tecnologia” (FCT), Portugal, grants reference PTDC/SAU-FCF/66421/2006 and PTDC/SAU-FCF/108056/2008, and cofinanced by COMPETE–Programa Operacional Factores de Competitividade, QREN, and the European Union (FEDER–Fundo Europeu de Desenvolvimento Regional). CNC is supported by project PEst-C/SAU/LA0001/2013-2014. C. Lopes and M. Ribeiro are supported by Ph.D. fellowships from FCT (SFRH/BD/51192/2010 and SFRH/BD/41285/2007, respectively). A. I. Duarte was supported by a postdoctoral fellowship from FCT (SFRH/BPD/26872/2006). The authors would like to thank to Dr. Sancha Santos (CNC and Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal) for the support with HPLC measurement of adenine nucleotides and to Dr. Mahmoud Pouladi (Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada) for critical revision of the manuscript and Dr. João Pereira (Faculty of Medicine, University of Coimbra, Coimbra, Portugal) for support in statistical analysis.

Conflicts of Interest Statement

The authors declare that they have no conflicts of interest.

Supplementary material

12035_2013_8585_Fig9_ESM.jpg (140 kb)
Figure S1

Influence of IGF-1 intranasal administration on open-field exploration on YAC128 and WT mice. YAC128 and WT littermates (n = 5–10 mice for treatment group and for genotype) were tested in an open-field activity box over a period of 30 min as described in “Materials and Methods.” Locomotor horizontal activity was recorded and analyzed for maximal (A) and mean velocity (B) (cm/s), distance travelled (cm) (C), slow movements (MS) (D), and fast movements (MF) (E) (% of total movement), time spent in central square (s) (F), rearings (G), and resting time (RT) (s) (H). There was no effect of genotype or treatment on open-field performance, except maximal velocity, which increased in the YAC128 mice IGF-1 treated [F(7,50) = 9.27, p < 0.01]. Data are the mean ± SEM of the indicated number of animals. (JPEG 140 kb)

12035_2013_8585_MOESM1_ESM.tif (4.3 mb)
High resolution image (TIFF 4.32 MB)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Carla Lopes
    • 1
  • Márcio Ribeiro
    • 1
  • Ana I. Duarte
    • 1
  • Sandrine Humbert
    • 2
    • 3
    • 4
  • Frederic Saudou
    • 2
    • 3
    • 4
  • Luís Pereira de Almeida
    • 1
    • 5
  • Michael Hayden
    • 6
  • A. Cristina Rego
    • 1
    • 7
  1. 1.CNC-Center for Neuroscience and Cell Biology and Faculty of MedicineUniversity of CoimbraCoimbraPortugal
  2. 2.Institut CurieParisFrance
  3. 3.INSERM U1005ParisFrance
  4. 4.CNRS UMR 3306OrsayFrance
  5. 5.Faculty of Pharmacy, University of CoimbraCoimbraPortugal
  6. 6.Centre for Molecular Medicine and Therapeutics, Department of Medical GeneticsUniversity of British ColumbiaVancouverCanada
  7. 7.Faculty of Medicine, University of CoimbraCoimbraPortugal

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