The Receptor for Advanced Glycation Endproducts (RAGE) and Mediation of Inflammatory Neurodegeneration

Abstract

Besides its role in RAGE-DIAPH1-mediated inflammation, DIAPH1 is a dynamic mediator of actin cytoskeleton stability and rearrangement, as well as a regulator of transcription factors [15,34-36]. It was recently reported that DIAPH1 was highly expressed in human gliomas; however, the specific details of DIAPH1 expression, including the cellular localization and the potential DIAPH1-mediated mechanisms of in vivo dysfunction in the rodent or human CNS, have not been elucidated [37]. Beyond this report, very little is known about DIAPH1 expression patterns and functions in the CNS of normal or degenerating models or humans; there are no known SNPs in DIAPH1 that increase or decrease neurodegenerative disease risk. However, the impact of RAGE-DIAPH1 signal transduction in peripheral cells exhibits prominent overlap with the patterns of cellular dysfunction observed in neurodegeneration, including the increased production of ROS and pro-inflammatory cytokines and the downregulation of homeostatic molecules, such as neurotrophins and cholesterol/lipid handlers. This signaling culminates in significant alterations in critical cellular functions, such as migration, phagocytosis, replication and cell death, particularly in cells of myeloid and endothelial origin, but also in neurons [4,12,38-40].