Role and Therapeutic Potential of RAGE Signaling in Neurodegeneration

Abstract: Activation of the receptor for advanced glycation end products (RAGE) has been shown to play an active role in the development of multiple neurodegenerative diseases, including Alz-heimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Although originally iden-tified as a receptor for advanced glycation end products, RAGE is a pattern recognition receptor able to bind multiple ligands. The final outcome of RAGE signaling is defined in a context and cell type specific manner and can exert both neurotoxic and neuroprotective functions. Contributing to the complexity of the RAGE signaling network, different RAGE isoforms with distinctive signaling capabilities have been described. Moreover, multiple RAGE ligands bind other receptors and RAGE antagonism can significantly affect their signaling. Here, we discuss the outcome of cell-type specific RAGE signaling in neurodegenerative pathologies. In addition, we will review the dif-ferent approaches that have been developed to target RAGE signaling and their therapeutic poten-tial. A clear understanding of the outcome of RAGE signaling in a cell type- and disease-specific manner would contribute to advancing the development of new therapies targeting RAGE. The abil-ity to counteract RAGE neurotoxic signaling while preserving its neuroprotective effects would be critical for the success of novel therapies targeting RAGE signaling.