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Molecular Neurobiology

, Volume 56, Issue 2, pp 935–953 | Cite as

Early Downregulation of p75NTR by Genetic and Pharmacological Approaches Delays the Onset of Motor Deficits and Striatal Dysfunction in Huntington’s Disease Mice

  • Nuria Suelves
  • Andrés Miguez
  • Saray López-Benito
  • Gerardo García-Díaz Barriga
  • Albert Giralt
  • Elena Alvarez-Periel
  • Juan Carlos Arévalo
  • Jordi Alberch
  • Silvia Ginés
  • Verónica BritoEmail author
Article
  • 296 Downloads

Abstract

Deficits in striatal brain-derived neurotrophic factor (BDNF) delivery and/or BDNF/tropomyosin receptor kinase B (TrkB) signaling may contribute to neurotrophic support reduction and selective early degeneration of striatal medium spiny neurons in Huntington’s disease (HD). Furthermore, we and others have demonstrated that TrkB/p75NTR imbalance in vitro increases the vulnerability of striatal neurons to excitotoxic insults and induces corticostriatal synaptic alterations. We have now expanded these studies by analyzing the consequences of BDNF/TrkB/p75NTR imbalance in the onset of motor behavior and striatal neuropathology in HD mice. Our findings demonstrate for the first time that the onset of motor coordination abnormalities, in a full-length knock-in HD mouse model (KI), correlates with the reduction of BDNF and TrkB levels, along with an increase in p75NTR expression. Genetic normalization of p75NTR expression in KI mutant mice delayed the onset of motor deficits and striatal neuropathology, as shown by restored levels of striatal-enriched proteins and dendritic spine density and reduced huntingtin aggregation. We found that the BDNF/TrkB/p75NTR imbalance led to abnormal BDNF signaling, manifested as a diminished activation of TrkB-phospholipase C-gamma pathway but upregulation of c-Jun kinase pathway. Moreover, we confirmed the contribution of the proper balance of BDNF/TrkB/p75NTR on HD pathology by a pharmacological approach using fingolimod. We observed that chronic infusion of fingolimod normalizes p75NTR levels, which is likely to improve motor coordination and striatal neuropathology in HD transgenic mice. We conclude that downregulation of p75NTR expression can delay disease progression suggesting that therapeutic approaches aimed to restore the balance between BDNF, TrkB, and p75NTR could be promising to prevent motor deficits in HD.

Keywords

Huntington’s disease p75NTR TrkB BDNF Motor deficits onset Striatal pathology 

Abbreviations

A2AR

adenosine receptor type 2A

BDNF

brain-derived neurotrophic factor

DARPP32

dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa

HD

Huntington’s disease

Htt

huntingtin

JNK

c-Jun kinase

KI

knock-in

PLCγ

phospholipase C gamma

PDE10A

phosphodiesterase 10A

mHtt

mutant huntingtin

MSN

medium spiny neuron

WT

wild type

Notes

Acknowledgements

We are very grateful to Ana Lopez and Maria Teresa Muñoz for technical assistance, Dr. Teresa Rodrigo and the staff of the animal care facility (Facultat de Psicologia Universitat de Barcelona), and Dr. Maria Calvo, Anna Bosch, and Elisenda Coll from the Advanced Optical Microscopy Unit from Scientific and Technological Centers from University of Barcelona for their support and advice with confocal technique.

Authors’ Contributions

N.S contributed to the design and carried out the biochemical and immunohistochemical studies, analyzed, interpreted data, and participated in the manuscript draft. A.M contributed to the design and carried out the pharmacological studies in R6/1 mice, analyzed, and interpreted data. S.L.B contributed to the design and carried out the ELISA studies, as well as analyzed and interpreted data. G.G.D.B contributed to the design and carried out the biochemical studies in the R6/1 mice, as well as analyzed and interpreted data. A.G participated in behavioral studies in the KI:p75+/− mice, as well as analyzed and interpreted data. E.A.P carried out immunohistochemistry. J.C.A revised and commented the manuscript. J.A revised and commented the manuscript. S.G contributed to data interpretation, to experimental design, and to the manuscript draft. V.B conceived the study, contributed to the design and carried out behavioral and dendritic spine studies, analyzed and interpreted data, wrote the manuscript, and edited the document. All authors read and approved the final manuscript.

Funding

This work was supported by the Ministerio de Ciencia e Innovación (SAF-2014-57160R to J.A and SAF2015-67474-R; MINECO/FEDER to S.G), the Centro de Investigaciones Biomédicas en Red sobre Enfermedades Neurodegenerativas (CIBERNED), and the Cure Huntington’s Disease Initiative (CHDI A-3468).

Compliance with Ethical Standards

Experimental procedures were approved by the Local Ethical Committee of the University of Barcelona (99/01) and the Generalitat de Catalunya (00/1094), following European (2010/63/UE) and Spanish (RD 1201/2005) regulations for the care and use of laboratory animals.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1126_Fig9_ESM.png (64 kb)
Supplemental Figure 1:

No altered expression of p75NTR and BDNF levels in the cortex of KI mice. Representative immunoblots showing the levels of p75NTR in cortical extracts obtained from WT, p75+/-, KI and KI:p75+/- mice at 6 months of age (A) and mature BDNF (mBDNF) in cortical extracts obtained from WT, p75+/-, KI and KI:p75+/- mice at 6, 8 and 10 months of age (B). Tubulin was used as loading control. Histograms represent relative protein levels expressed as percentage of WT values. All data are shown as the mean ± SEM (n= 5-7 mice/genotype/age). Data were analyzed by one-way ANOVA followed by Tukey's test. *P <0.05 compared with WT. (GIF 44 kb)

12035_2018_1126_MOESM1_ESM.tif (26.1 mb)
High Resolution Image (TIF 26704 kb)
12035_2018_1126_Fig10_ESM.png (38 kb)
Supplemental Figure 2:

Normalization of p75NTR expression in KI mice do not affect dendritic spine density at early disease stages. Representative dendrites of medium spiny neurons from WT, p75+/–, KI, and KI:p75+/– mice at 3 months of age. Scale Bar: 2 μm. Histograms show quantitative analysis of dendritic spine density per micrometer of dendritic length. Data are shown as the mean ± SEM (90–100 dendrites; n= 3–5 animals per genotype). Data were analyzed by one-way ANOVA followed by Tukey's test. (GIF 24 kb)

12035_2018_1126_MOESM2_ESM.tif (13.2 mb)
High Resolution Image (TIF 13509 kb)
12035_2018_1126_Fig11_ESM.png (57 kb)
Supplemental Figure 3:

Antibody validation for the detection of mBDNF in striatal lysates. Western Blot analysis using Santa Cruz anti-BDNF antibody (N-20, rabbit) (A) or anti-BDNF antibody developed by Icosagen (clone3C1, mouse) (B) in striatal lysates from WT, BDNF+/- and BDNF-/- mice. Recombinant BDNF from Prepotech was used as positive control. (GIF 35 kb)

12035_2018_1126_MOESM3_ESM.tif (18.4 mb)
High Resolution Image (TIF 18821 kb)
12035_2018_1126_Fig12_ESM.png (56 kb)
Supplemental Figure 4:

CREB phosphorylation is not altered in KI mice along disease progression. Representative immunoblots showing the levels of pCREB (ser133) and CREB with tubulin as loading control in striatal extracts obtained from WT, p75+/-, KI and KI:p75+/- mice at 6, 8 and 10 months of age. Histograms represent the relative ratios of pCREB/CREB expressed as percentage of WT values. All data are shown as the mean ± SEM (n= 5-7 mice/genotype/age). Data were analyzed by one-way ANOVA followed by Tukey's test. (GIF 39 kb)

12035_2018_1126_MOESM4_ESM.tif (17.8 mb)
High Resolution Image (TIF 18188 kb)
12035_2018_1126_Fig13_ESM.png (255 kb)
Supplemental Figure 5:

Neuronal death is not detected in KI mice. Representative photomicrographs showing no cleaved Caspase-3 (red) positive-stained cells in WT or KI naïve mice at 8 months of age. Mice which had undergone physical lesion in the corticostriatal region causing cell apoptosis were used as positive control of the immunostaining. Scale Bar: 100 μm. (GIF 181 kb)

12035_2018_1126_MOESM5_ESM.tif (26.3 mb)
High Resolution Image (TIF 26924 kb)
12035_2018_1126_Fig14_ESM.png (140 kb)
Supplemental Figure 6:

Cortical thickness is not altered by p75NTR levels. (A) Representative photomicrographs showing normal cortical thickness (dashed lines) in WT, p75+/-, KI and KI:p75+/- mice at 8 months of age. Scale Bar: 500 μm. (B) Histogram represents quantification of motor cortex thickness (M1). Data are shown as the mean ± SEM (n=5 mice/group). Data were analyzed by one-way ANOVA followed by Tukey's test. (TIF 26924 kb) (GIF 96 kb)

12035_2018_1126_MOESM6_ESM.tif (21.6 mb)
High Resolution Image (TIF 22083 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Nuria Suelves
    • 1
    • 2
    • 3
  • Andrés Miguez
    • 1
    • 2
    • 3
  • Saray López-Benito
    • 4
    • 5
  • Gerardo García-Díaz Barriga
    • 1
    • 2
    • 3
  • Albert Giralt
    • 1
    • 2
    • 3
  • Elena Alvarez-Periel
    • 1
    • 2
    • 3
  • Juan Carlos Arévalo
    • 4
    • 5
  • Jordi Alberch
    • 1
    • 2
    • 3
  • Silvia Ginés
    • 1
    • 2
    • 3
  • Verónica Brito
    • 1
    • 2
    • 3
    Email author
  1. 1.Departament de Biomedicina, Facultat de Medicina, Institut de NeurosciènciesUniversitat de BarcelonaBarcelonaSpain
  2. 2.Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)BarcelonaSpain
  3. 3.Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)MadridSpain
  4. 4.Department of Cell Biology and Pathology, Instituto de Neurociencias de Castilla y León (INCyL)University of SalamancaSalamancaSpain
  5. 5.Institute of Biomedical Research of Salamanca (IBSAL)SalamancaSpain

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