Temporospatial expression pattern of RAGE and its ligands in a rat model of Huntington’s disease

Abstract

The receptor for advanced glycation-endproducts (RAGE) is a transmembrane multi-ligand receptor that has a large repertoire of ligands including S100B and CML. Its activation leads to a series of signal transduction pathways including NFκB which its production can positively feedback to the production of more RAGE. RAGE and its ligands are also known for a similar positive feedback mechanism that can be exerted on each other. This particular property of RAGE allows it to be up-regulated with its ligand in a prolonged and sustained manner. Although RAGE-ligand interaction could have beneficial roles, its prolonged activation under pathological conditions, can often lead to prolonged inflammation which is implicated in diseases such as diabetes and Alzheimer’s disease. The pathological hallmark of Alzheimer’s disease beta-amyloid was found to be one of the ligands for RAGE. Huntington’s disease (HD) which is also a progressive neurodegenerative disease is thought to be associated with RAGE. Unsurprisingly, a study published in our laboratory found a positive association between RAGE expression and HD progression in the striatum. This suggests a potential involvement of RAGE in the pathologies underlying HD. Thus it would be interesting to establish an animal model for assessing RAGE expression in HD for future therapeutic and functional studies. Having an opportunity of obtaining a rat model of Huntington’s disease (tgHD rat), the temporospatial pattern of expression of RAGE and its ligands in this model were assessed and compared to that in human HD brains. Immunohistochemistry was carried out on rat striatum or caudate-putamen sections. Semi-quantitative cell counting was conducted to determine RAGE expression, RAGE-S100B colocalization and RAGE-CML colocalization. The result showed that RAGE expression and RAGE-CML colocalization was higher in the tgHD rats than that in the controls but in all age groups used, suggesting a non-progressive nature which is not seen in humans HD brains. Moreover, the spatial pattern in the tgHD differs than that of in the human HD brain. Therefore, the validity of this HD model to model HD has to be reconsidered.