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Experimental therapeutics: preclinical
B16 NGF improves the spatial working memory in R6/1 Huntington's disease transgenic mice through the augmentation of cholinergic function and neurogenesis
  1. H Zhang1,
  2. G Petit1,
  3. P M Gaughwin1,
  4. X Zuo1,
  5. S Ranganathan1,
  6. R Smith1,
  7. L Roybon1,
  8. P Brundin1,
  9. W C Mobley2,
  10. J-Y Li1
  1. 1Department of Experimental Medical Science, Lund University, Lund, Sweden
  2. 2Department of Neurology and Neurological Sciences and the Program in Neuroscience, Stanford University, Stanford, California, USA

Abstract

Background Our previous studies demonstrated that cholinergic dysfunction occurred in transgenic mouse models and patients with Huntington's disease (HD). This may contribute to the cognitive deficits in the disease. Nerve growth factor (NGF) is an essential regulator of cholinergic neuronal survival and neurotransmission. We hypothesise that the cholinergic dysfunction may result from a failure of NGF availability and/or of retrograde NGF signalling.

Aim The project aimed to study whether administration of NGF could rescue cholinergic deficits in the models of HD.

Methods/techniques Intraventricular infusion. Star maze tests and immunohistochemistry.

Results Two weeks after intracerebroventricular NGF infusion, we performed behavioural tests using a starmaze setup, and injection of BrdU to assess cell proliferation and differentiation. The animals were killed 4 weeks after the NGF administration. Immunohistochemistry was performed. We observed significant improvement of the deteriorated spatial working memory in NGF treated R6/1 HD mice. Moreover, we unravel the underlying mechanisms by demonstrating a normalisation of cholinergic function and increased neurogenesis in the hippocampus of NGF treated R6/1 mice.

Conclusion The study provided rationales for early therapeutic intervention with NGF in HD.

  • Huntington disease
  • cholinergic function
  • NGF
  • therapy
  • neuroprotection

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