Li Wen, Chen Qiuping, Peng Chengjie, Yang Dan, Liu Si, Lv Yanwen, Jiang Langqi, Xu Shijun, Huang Lihua
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China.
Int J Mol Sci. 2025 Jan 5;26(1):403. doi: 10.3390/ijms26010403.
The Receptor for Advanced Glycation End Products (RAGE), part of the immunoglobulin superfamily, plays a significant role in various essential functions under both normal and pathological conditions, especially in the progression of Alzheimer's disease (AD). RAGE engages with several damage-associated molecular patterns (DAMPs), including advanced glycation end products (AGEs), beta-amyloid peptide (Aβ), high mobility group box 1 (HMGB1), and S100 calcium-binding proteins. This interaction impairs the brain's ability to clear Aβ, resulting in increased Aβ accumulation, neuronal injury, and mitochondrial dysfunction. This further promotes inflammatory responses and oxidative stress, ultimately leading to a range of age-related diseases. Given RAGE's significant role in AD, inhibitors that target RAGE and its ligands hold promise as new strategies for treating AD, offering new possibilities for alleviating and treating this serious neurodegenerative disease. This article reviews the various pathogenic mechanisms of AD and summarizes the literature on the interaction between RAGE and its ligands in various AD-related pathological processes, with a particular focus on the evidence and mechanisms by which RAGE interactions with AGEs, HMGB1, Aβ, and S100 proteins induce cognitive impairment in AD. Furthermore, the article discusses the principles of action of RAGE inhibitors and inhibitors targeting RAGE-ligand interactions, along with relevant clinical trials.
晚期糖基化终末产物受体（RAGE）是免疫球蛋白超家族的一部分，在正常和病理条件下的各种基本功能中发挥着重要作用，尤其是在阿尔茨海默病（AD）的进展过程中。RAGE与多种损伤相关分子模式（DAMPs）相互作用，包括晚期糖基化终末产物（AGEs）、β-淀粉样肽（Aβ）、高迁移率族蛋白B1（HMGB1）和S100钙结合蛋白。这种相互作用损害了大脑清除Aβ的能力，导致Aβ积累增加、神经元损伤和线粒体功能障碍。这进一步促进了炎症反应和氧化应激，最终导致一系列与年龄相关的疾病。鉴于RAGE在AD中的重要作用，靶向RAGE及其配体的抑制剂有望成为治疗AD的新策略，为缓解和治疗这种严重的神经退行性疾病提供了新的可能性。本文综述了AD的各种致病机制，并总结了关于RAGE与其配体在各种AD相关病理过程中相互作用的文献，特别关注RAGE与AGEs、HMGB1、Aβ和S100蛋白相互作用诱导AD认知障碍的证据和机制。此外，本文还讨论了RAGE抑制剂和靶向RAGE-配体相互作用的抑制剂的作用原理以及相关的临床试验。
