Department of Physiology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.
Mol Cell Biochem. 2019 Sep;459(1-2):95-112. doi: 10.1007/s11010-019-03553-4. Epub 2019 May 11.
Numerous hypotheses including amyloid cascade, cholinergic, and oxidative have been proposed for pathogenesis of Alzheimer's disease (AD). The data suggest that advanced glycation end products (AGEs) and its receptor RAGE (receptor for AGE) are involved in the pathogenesis of AD. AGE-RAGE stress, defined as a balance between stressors (AGE, RAGE) and anti-stressors (sRAGE, AGE degraders) in favor of stressors, has been implicated in pathogenesis of diseases. AGE and its interaction with RAGE-mediated increase in the reactive oxygen species (ROS) damage brain because of its increased vulnerability to ROS. AGE and ROS increase the synthesis of amyloid β (Aβ) leading to deposition of Aβ and phosphorylation of tau, culminating in formation of plaques and neurofibrillary tangles. ROS increase the synthesis of Aβ, high-mobility group box 1(HMGB1), and S100 that interacts with RAGE to produce additional ROS resulting in enhancement of AD pathology. Elevation of ROS precedes the Aβ plaques formation. Because of involvement of AGE and RAGE in AD pathology, the treatment should be targeted at lowering AGE levels through reduction in consumption and formation of AGE, and lowering expression of RAGE, blocking of RAGE ligand binding, increasing levels of soluble RAGE (sRAGE), and use of antioxidants. The above treatment aspect of AD is lacking. In conclusion, AGE-RAGE stress initiates, and Aβ, HMGB1, and S100 enhance the progression of AD. Reduction of levels of AGE and RAGE, elevation of sRAGE, and antioxidants would be beneficial therapeutic modalities in the prevention, regression, and slowing of progression of AD.
已经提出了许多假说，包括淀粉样蛋白级联、胆碱能和氧化应激等，来解释阿尔茨海默病（AD）的发病机制。有数据表明，晚期糖基化终产物（AGE）及其受体 RAGE（AGE 受体）参与了 AD 的发病机制。AGE-RAGE 应激，定义为应激源（AGE、RAGE）与抗应激源（sRAGE、AGE 降解物）之间的平衡有利于应激源，与疾病的发病机制有关。AGE 及其与 RAGE 介导的活性氧（ROS）增加的相互作用会损害大脑，因为大脑对 ROS 的易感性增加。AGE 和 ROS 增加了淀粉样蛋白β（Aβ）的合成，导致 Aβ沉积和 tau 磷酸化，最终形成斑块和神经原纤维缠结。ROS 增加了 Aβ、高迁移率族蛋白 B1（HMGB1）和 S100 的合成，这些物质与 RAGE 相互作用产生额外的 ROS，从而增强 AD 病理学。ROS 的升高先于 Aβ 斑块的形成。由于 AGE 和 RAGE 参与了 AD 的发病机制，治疗方法应该针对降低 AGE 水平，包括减少 AGE 的消耗和形成，降低 RAGE 的表达，阻断 RAGE 配体结合，增加可溶性 RAGE（sRAGE）的水平，并使用抗氧化剂。目前缺乏针对 AD 的上述治疗方法。总之，AGE-RAGE 应激启动了 AD 的发生，而 Aβ、HMGB1 和 S100 则促进了 AD 的进展。降低 AGE 和 RAGE 的水平、提高 sRAGE 和抗氧化剂的水平将是预防、逆转和减缓 AD 进展的有益治疗方法。
