Neuropharmacology Research Laboratory, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, Selangor 46150, Malaysia.
Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Cells. 2020 Feb 7;9(2):383. doi: 10.3390/cells9020383.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.
阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，也是痴呆症的主要原因，其明确的病理特征是淀粉样蛋白-β（Aβ）和神经原纤维缠结（NFTs）的积累。AD 目前尚无治愈方法，是全球严重的健康问题，这反映了其发病机制的复杂性。最近的证据表明，神经炎症是淀粉样蛋白沉积、Tau 病理学和神经退行性变之间的联系。高迁移率族蛋白 B1（HMGB1）是神经炎症反应的启动子和激活剂，它与包括 AD 在内的神经退行性疾病的发病机制有关。HMGB1 是一种典型的损伤相关分子模式（DAMP）蛋白，主要通过与晚期糖基化终产物受体（RAGE）和 Toll 样受体 4（TLR4）结合来发挥其生物学活性。RAGE 和 TLR4 是先天免疫系统的关键组成部分，两者都与 HMGB1 结合。在实验性 AD 模型中针对 HMGB1、RAGE 和 TLR4 的靶向治疗已证明通过抑制神经炎症、减少 Aβ 负荷和产生、改善空间学习和抑制小胶质细胞刺激来阻止 AD 进展具有有益作用。本文讨论了 HMGB1 及其受体信号在神经炎症和 AD 发病机制中的作用，为其治疗靶向的有益作用提供了证据。
