Alzheimer's disease (AD) is a progressively neurodegenerative disease with typical hallmarks of amyloid β (Aβ) plaque accumulation, neurofibrillary tangle (NFT) formation and neuronal death extension. In AD brain, activated microglia phagocytose Aβ and neuronal debris, but also aggravate inflammation stress by releasing inflammatory factors and cytotoxins. Improving microglia on Aβ catabolism and neuroinflammatory intervention is thus believed to be a promising therapeutic strategy for AD. AMP-activated protein kinase (AMPK) is highly expressed in microglia with AMPKα1 being tightly implicated in neuroinflammatory events. Since indirect AMPKα1 activators may cause side effects with undesired intracellular AMP/ATP ratio, we focused on direct AMPKα1 activator study by exploring its potential function in ameliorating AD-like pathology of AD model mice. Here, we reported that direct AMPKα1 activator DW14006 (2-(3-(7-chloro-6-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinolin-3-yl)phenyl)acetic acid) effectively improved learning and memory impairments of APP/PS1 mice, and the underlying mechanisms have been intensively investigated. DW14006 reduced amyloid plaque deposition by promoting microglial o-Aβ42 phagocytosis and ameliorated innate immune response by polarizing microglia to an anti-inflammatory phenotype. It selectively enhanced microglial phagocytosis of o-Aβ42 by upgrading scavenger receptor CD36 through AMPKα1/PPARγ/CD36 signaling and suppressed inflammation by AMPKα1/IκB/NFκB signaling. Together, our work has detailed the crosstalk between AMPKα1 and microglia in AD model mice, and highlighted the potential of DW14006 in the treatment of AD.

中文翻译：

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DW14006 作为直接 AMPKα1 激活剂通过调节小胶质细胞吞噬和神经炎症改善 AD 模型小鼠的病理

阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，具有淀粉样蛋白 β (Aβ) 斑块积聚、神经原纤维缠结 (NFT) 形成和神经元死亡扩展的典型标志。在 AD 大脑中，激活的小胶质细胞吞噬 Aβ 和神经元碎片，但也会通过释放炎症因子和细胞毒素来加剧炎症应激。因此，改善小胶质细胞对 Aβ 分解代谢和神经炎症干预被认为是一种很有前途的 AD 治疗策略。AMP 活化蛋白激酶 (AMPK) 在小胶质细胞中高度表达，AMPKα1 与神经炎症事件密切相关。由于间接 AMPKα1 激活剂可能会导致不良的细胞内 AMP/ATP 比率的副作用，我们通过探索其在改善 AD 模型小鼠的 AD 样病理方面的潜在功能，专注于直接 AMPKα1 激活剂的研究。在这里，我们报道了直接 AMPKα1 激活剂 DW14006 (2-(3-(7-chloro-6-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-二氢喹啉-3-基）苯基）乙酸）有效改善了 APP/PS1 小鼠的学习和记忆障碍，其潜在机制已得到深入研究。DW14006 通过促进小胶质细胞 o-Aβ42 吞噬作用减少淀粉样蛋白斑块沉积，并通过将小胶质细胞极化为抗炎表型来改善先天免疫反应。它通过 AMPKα1/PPARγ/CD36 信号传导升级清道夫受体 CD36，选择性地增强小胶质细胞对 o-Aβ42 的吞噬作用，并通过 AMPKα1/IκB/NFκB 信号传导抑制炎症。一起，