2. Academic Validation
  3. DW14006 as a direct AMPKα1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation

DW14006 as a direct AMPKα1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation

  • Brain Behav Immun. 2020 Nov;90:55-69. doi: 10.1016/j.bbi.2020.07.041.
Jianlu Lv 1,  Wei Wang 2,  Xialin Zhu 1,  Xiaoju Xu 1,  Qiuying Yan 1,  Jian Lu 1,  Xiaofan Shi 3,  Zhengyu Wang 4,  Jinpei Zhou 4,  Xi Huang 1,  Jiaying Wang 5,  Wenhu Duan 6,  Xu Shen 7
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
  • 3 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
  • 5 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: wangjy@njucm.edu.cn.
  • 6 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China. Electronic address: whduan@simm.ac.cn.
  • 7 Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: xshen@njucm.edu.cn.
PMID: 32739363 DOI: 10.1016/j.bbi.2020.07.041
Abstract

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.

Keywords

AMPKα1; Alzheimer’s disease; DW14006; Microglia; Neuro-inflammation; Phagocytosis.

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