Research reportExpression of the receptor for advanced glycation end products in Huntington's disease caudate nucleus
Introduction
The receptor for advanced glycation end products, known as RAGE, was first described in 1992 by Neeper et al. [15]. The binding of the first known ligand for RAGE, advanced glycation end products (AGEs), was reported in association with chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Further ligands for RAGE have subsequently been identified including amyloid fibrils, amphoterin and S100/calgranulins. Within tissues so far described, over-expression of the receptor has always been associated with the accumulation of the ligand. This accumulation of ligand in diseased tissues leads to sustained receptor expression through positive feedback and prolonged cell activation, which subsequently plays a significant role in a range of chronic disorders. For example, increased levels of AGEs in diabetes contributes to renal insufficiency; increase in the ligand amphoterin in tumors is associated with tumor metastasis, while S100/calgranulins found at sites of inflammation contribute to the inflammatory response [21].
In 1996, amyloid-β was identified as a ligand for RAGE [28]. Since then, the role of RAGE in the brain has attracted further interest. Tohgi et al. [22] investigated the changes in the methylation status of cytosines in the promoter region of RAGE in autopsy human cortex. Results showed that the number of methylcytosines at transcription factor binding sites decreased with age. Methylation at the promoter region normally repress transcriptional activity. This reduction may in turn increase the expression of RAGE, suggesting a role for RAGE in aging of the brain. Another study investigated the expression of RAGE and the ligand S100B in rat brain after treatment with the antidepressant fluoxatine [12]. RAGE expression was found to be co-localized with BrdU positive proliferating cells in the hippocampus. This RAGE expression in neuronal cells or neuronal precursors and its activation by S100B has been suggested as a possible mechanism promoting cell survival in the brain. However, it is the RAGE mediated amyloid-β neurotoxicity in the neurodegenerative disease Alzheimer's disease (AD) that has been most intensively studied. RAGE has been found in neurons, astrocytes and microglia in AD brain [10], [19]. In cell culture, amyloid-β binds to RAGE mediating changes in cellular properties including expression of macrophage-colony stimulating factor (M-CSF), activation of NF-κB and caspase 3, and induction of DNA fragmentation, which finally leads to sustained microglia activation and RAGE-dependent apoptosis of neurons [5], [28]. Furthermore, a recent study by Deane et al. [2] showed that RAGE mediates amyloid-β peptide transport across the blood–brain barrier (BBB) and its accumulation in the brain. To date, RAGE expression has been described in only one other neurodegenerative disease, Creutzfeldt–Jakob disease [20]; there have been no reports of RAGE in Huntington's disease (HD) brain. We have investigated RAGE expression, using immunohistochemistry, in grades 1–4 HD and age-, sex-matched control human brains.
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Subjects and specimens
Human brain tissue was obtained from the New Zealand Neurological Foundation Human Brain Bank at the University of Auckland. The full consent of all families was given at the time of autopsy and approval for the study obtained through the University of Auckland Human Subjects Ethics Committee. All 12 HD cases were examined and pathologically verified by an independent pathologist for extent of neurodegeneration and assigned a grade from 0 (minimal, G0) to 4 (extensive, G4) according to the
Identification of RAGE positive cells
Two morphologically distinct cell types, positive for RAGE, were identified in HD CN; neurons and astrocytes. In Fig. 1, RAGE immunoreactivity in the cytoplasm of neuron-like cells (A, arrowheads), shown in red, is co-localized with calbindin immunoreactivity, shown in green, in the same cells (B, arrowheads). A combination of the images produces a yellow color at the site of co-localization (Fig. 1C, arrowheads). Co-localization of RAGE and GFAP was also found. Fig. 1D shows the red RAGE
Discussion
RAGE is a multiligand receptor which recognizes families of ligands rather than a single polypeptide. In 1996, Yan et al. [28] first reported RAGE as a receptor for amyloid-β, the misfolded protein which is rich in β-sheets and accumulates in AD brain. Several years later, other peptides with high β-sheet content such as amylin, amyloid A and prion-derived peptide were reported to also bind to RAGE [29]. Interestingly, none of these peptides bound to RAGE in their random conformation; only the
Acknowledgements
This work was supported by the New Zealand Neurological Foundation. The authors wish to thank the Director of the New Zealand Neurological Foundation Human Brain Bank, Professor Richard Faull and Dr. Henry Waldvogel for provision of the human brain tissue. Imaging was carried out in the Biomedical Imaging Research Unit in the Faculty of Medical and Health Sciences.
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