CD200 is up-regulated in R6/1 transgenic mouse model of Huntington's disease.

Andrea Comella Bolla,Carme Solà,Andres Miguez,Tony Valente,Silvia Gines,Veronica Brito,Marco Straccia,Josep M Canals

doi:10.1371/journal.pone.0224901

Abstract

In Huntington’s disease (HD), striatal medium spiny neurons (MSNs) are particularly sensitive to the presence of a CAG repeat in the huntingtin (HTT) gene. However, there are many evidences that cells from the peripheral immune system and central nervous system (CNS) immune cells, namely microglia, play an important role in the etiology and the progression of HD. However, it remains unclear whether MSNs neurodegeneration is mediated by a non-cell autonomous mechanism. The homeostasis in the healthy CNS is maintained by several mechanisms of interaction between all brain cells. Neurons can control microglia activation through several inhibitory mechanisms, such as the CD200–CD200R1 interaction. Due to the complete lack of knowledge about the CD200–CD200R1 system in HD, we determined the temporal patterns of CD200 and CD200R1 expression in the neocortex, hippocampus and striatum in the HD mouse models R6/1 and HdhQ111/7 from pre-symptomatic to manifest stages. In order to explore any alteration in the peripheral immune system, we also studied the levels of expression of CD200 and CD200R1 in whole blood. Although CD200R1 expression was not altered, we observed and increase in CD200 gene expression and protein levels in the brain parenchyma of all the regions we examined, along with HD pathogenesis in R6/1 mice. Interestingly, the expression of CD200 mRNA was also up-regulated in blood following a similar temporal pattern. These results suggest that canonical neuronal–microglial communication through CD200–CD200R1 interaction is not compromised, and CD200 up-regulation in R6/1 brain parenchyma could represent a neurotrophic signal to sustain or extend neuronal function in the latest stages of HD as pro-survival mechanism.

Highlights

Huntington’s disease (HD) is an autosomal dominant genetic disease caused by a CAG repeat expansion over 37 repeats in the HTT gene
We recently showed that fingolimod (FTY720), a structural analog of sphingosine that act as an immunomodulatory drug for multiple sclerosis (MS), can reduce astroglial reactivity in R6/1 mice acting through S1P receptor [13]
We assessed the expression of CD200–CD200R1 in FTY720-treated animals, as we recently reported that the chronic treatment of this immunomodulating drug attenuates astrogliosis and prevents dendritic spines loss in the hippocampus of R6/1 mice [13]

Summary

Introduction

HD is an autosomal dominant genetic disease caused by a CAG repeat expansion over 37 repeats in the HTT gene. HD causes neurodegeneration at a lesser extent in cortical and hippocampal regions [3,4,5], which triggers cognitive impairment and psychiatric symptoms that precede motor dysfunction [6]. In the post-mortem HD brain, astrocytosis and microgliosis has been observed in caudate and the internal capsule with an increase complement biosynthesis by reactive microglia [10], which has been recently described as an important mechanism for early synaptic loss in Alzheimer’s disease (AD) [11]. Microglia activation in HD patient brains is detected years before HD clinical manifestation by magnetic resonance imaging (MRI), allowing to predict disease onset and correlating with disease progression [12]. The highest societal burden associated with HD is due to psychiatric symptoms, which prevalence is estimated between 33% and 76% during disease progression in humans [17]

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Results

Conclusion