Department of Medicine, Division of Geriatrics and Gerontology, University of Wisconsin- Madison, Madison, WI, USA.
Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, WI, USA.
Curr Drug Targets. 2022;23(12):1191-1209. doi: 10.2174/1389450123666220610171005.
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 celltype 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 advancing 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.
晚期糖基化终产物受体（RAGE）的激活已被证明在多种神经退行性疾病的发展中发挥着积极作用，包括阿尔茨海默病、帕金森病和肌萎缩侧索硬化症。尽管 RAGE 最初被鉴定为晚期糖基化终产物的受体，但它是一种模式识别受体，能够结合多种配体。RAGE 信号的最终结果是特定于上下文和细胞类型的，并可以发挥神经毒性和神经保护作用。RAGE 信号网络的复杂性导致了具有不同信号转导能力的不同 RAGE 异构体的描述。此外，多种 RAGE 配体与其他受体结合，RAGE 拮抗作用可显著影响它们的信号转导。在这里，我们讨论了特定于细胞类型的 RAGE 信号在神经退行性病理中的结果。此外，我们将回顾为靶向 RAGE 信号而开发的不同方法及其治疗潜力。明确了解 RAGE 信号在细胞类型和疾病特异性方面的结果将有助于推进针对 RAGE 的新疗法的发展。在保留其神经保护作用的同时拮抗 RAGE 神经毒性信号的能力对于针对 RAGE 信号的新型治疗方法的成功至关重要。
