DW14006 as a direct AMPK alpha 1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation

doi:10.1016/j.bbi.2020.07.041

	DW14006 as a direct AMPK alpha 1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation
	Lv, Jianlu 1; Wang, Wei 2,3; Zhu, Xialin 1; Xu, Xiaoju 1; Yan, Qiuying 1; Lu, Jian 1; Shi, Xiaofan 1,2; Wang, Zhengyu 4; Zhou, Jinpei 4; Huang, Xi 1
刊名	BRAIN BEHAVIOR AND IMMUNITY
	2020-11-01
卷号	90 页码:55-69
关键词	Alzheimer'sdisease Microglia AMPK alpha 1 DW14006 Phagocytosis Neuro-inflammation
ISSN号	0889-1591
DOI	10.1016/j.bbi.2020.07.041
通讯作者	Wang, Jiaying(wangjy@njucm.edu.cn) ; Duan, Wenhu(whduan@simm.ac.cn) ; Shen, Xu(xshen@njucm.edu.cn)
英文摘要	Alzheimer's disease (AD) is a progressively neurodegenerative disease with typical hallmarks of amyloid beta (A beta) plaque accumulation, neurofibrillary tangle (NFT) formation and neuronal death extension. In AD brain, activated microglia phagocytose A beta and neuronal debris, but also aggravate inflammation stress by releasing inflammatory factors and cytotoxins. Improving microglia on A beta 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 AMPK alpha 1 being tightly implicated in neuroinflammatory events. Since indirect AMPK alpha 1 activators may cause side effects with undesired intracellular AMP/ATP ratio, we focused on direct AMPK alpha 1 activator study by exploring its potential function in ameliorating AD-like pathology of AD model mice. Here, we reported that direct AMPK alpha 1 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-A beta 42 phagocytosis and ameliorated innate immune response by polarizing microglia to an anti-inflammatory phenotype. It selectively enhanced microglial phagocytosis of oA beta 42 by upgrading scavenger receptor CD36 through AMPK alpha 1/PPAR gamma/CD36 signaling and suppressed inflammation by AMPK alpha 1/I kappa B/NF kappa B signaling. Together, our work has detailed the crosstalk between AMPK alpha 1 and microglia in AD model mice, and highlighted the potential of DW14006 in the treatment of AD.
资助项目	National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; National Natural Science Foundation for Young Scientists of China[81703806] ; Postgraduate Research & Practice Innovation Program of Jiangsu Province[KYCX18_1600] ; Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica[JKLPSE201801] ; Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) ; Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine) ; Innovative Research Team of Six Talent Peaks Project in Jiangsu Province[TD-SWYY-013]
WOS关键词	NF-KAPPA-B ; AMELIORATES MEMORY IMPAIRMENT ; PROTEIN-KINASE ACTIVATION ; ALZHEIMERS-DISEASE MODEL ; ADENOSINE-MONOPHOSPHATE ; 5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIBONUCLEOSIDE ; HUMAN MONOCYTES ; DOWN-REGULATION ; MOUSE MODEL ; BETA
WOS研究方向	Immunology ; Neurosciences & Neurology ; Psychiatry
语种	英语
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS记录号	WOS:000577976900006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/291370]
专题	中国科学院上海药物研究所
通讯作者	Wang, Jiaying; Duan, Wenhu; Shen, Xu
作者单位	1.Nanjing Univ Chinese Med, Jiangsu Key Lab Pharmacol & Safety Evaluat Chines, Nanjing 210023, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.China Pharmaceut Univ, Dept Med Chem, 24 Tongjia Xiang, Nanjing 210009, Peoples R China
推荐引用方式 GB/T 7714	Lv, Jianlu,Wang, Wei,Zhu, Xialin,et al. DW14006 as a direct AMPK alpha 1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation[J]. BRAIN BEHAVIOR AND IMMUNITY,2020,90:55-69.
APA	Lv, Jianlu.,Wang, Wei.,Zhu, Xialin.,Xu, Xiaoju.,Yan, Qiuying.,...&Shen, Xu.(2020).DW14006 as a direct AMPK alpha 1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation.BRAIN BEHAVIOR AND IMMUNITY,90,55-69.
MLA	Lv, Jianlu,et al."DW14006 as a direct AMPK alpha 1 activator improves pathology of AD model mice by regulating microglial phagocytosis and neuroinflammation".BRAIN BEHAVIOR AND IMMUNITY 90(2020):55-69.