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 Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Although originally identified 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 different approaches that have been developed to target RAGE signaling and their therapeutic potential. A clear understanding of the outcome of RAGE signaling in a cell type- and disease-specific manner would contribute to advance the development of new therapies targeting RAGE. The ability to counteract RAGE neurotoxic signaling while preserving its neuroprotective effects would be critical for the success of novel therapies targeting RAGE signaling.

Is it all the RAGE? Defining the role of the receptor for advanced glycation end products in Parkinson's disease

“…This compound was demonstrated to be safe and well tolerated, but the phase III STEADFAST study concluded that PF-04494700 showed no efficacy and caused adverse effects at higher doses. Nevertheless, a post hoc analysis indicated a beneficial effect in AD patients with type 2 diabetes-which led to the initiation of a new phase 2 study (Kinscherf & Pehar, 2022).…”

“…This compound was demonstrated to be safe and well tolerated, but the phase III STEADFAST study concluded that PF‐04494700 showed no efficacy and caused adverse effects at higher doses. Nevertheless, a post hoc analysis indicated a beneficial effect in AD patients with type 2 diabetes—which led to the initiation of a new phase 2 study (Kinscherf & Pehar, 2022). Blocking peptides designed to interfere with RAGE dimerization recently emerged as a promising strategy, displaying potential benefits in models of atherosclerosis (Pickering et al, 2019) and metastatic cancer (Arumugam et al, 2012), while immune neutralization with specific anti‐RAGE has been tested in pre‐clinical models of sepsis (Gasparotto, Ribeiro, Bortolin, Somensi, Fernandes, et al, 2017; Lutterloh et al, 2007), atherosclerosis (Bro et al, 2008), and melanoma (Abe et al, 2004).…”

Specific antagonist of receptor for advanced glycation end‑products attenuates delirium‑like behaviours induced by sevoflurane anaesthesia with surgery in aged mice partially by improving damage to the blood‑brain barrier

“…Specifically, RAGEs are enriched at the lumina of microvascular endothelial cells and mediate circulating Aβ influx across the BBB, leading to Aβ deposition in brain parenchyma. RAGE activation is also involved in BBB damage in a variety of human brain disorders, including AD, Parkinson's disease (PD) and amyotrophic lateral sclerosis ( 13 , 28 ). However, to the best of our knowledge, the role of RAGE activation in BBB disruption under anaesthesia and surgery remains unclear.…”