Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy

doi:10.1016/j.neuropharm.2017.11.033

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第三研究室

	Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy
	Guo, Xiaodan 1,3; Lv, Jianlu 1,2,3; Lu, Jian 1,2,3; Fan, Lei 3; Huang, Xi 1; Hu, Lihong 1; Wang, Jiaying 1,2; Shen, Xu1,2,3
刊名	NEUROPHARMACOLOGY
	2018-03-01
卷号	130 页码:77-91
关键词	Alzheimer's disease Ginseng Autophagy BACE1 ER stress Amyloid beta Apoptosis APP/PS1 transgenic mice
ISSN号	0028-3908
DOI	10.1016/j.neuropharm.2017.11.033
文献子类	Article
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. Aggressive A beta accumulation promotes senile plaque formation and perturbs endoplasmic reticulum (ER) function to trigger the unfolded protein response (UPR) leading to neuronal apoptosis. The stress dependent activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) increases the phosphorylation of eukaryotic translation initiation factor-2 alpha (eIF2 alpha) to promote the preferential synthesis of beta-site APP cleavage enzyme 1 (BACE1) and A beta generation in turn. Additionally, dysfunction in autophagy has been reported to contribute to several neurodegenerative diseases including AD, and impairment in autophagy-mediated pathway may constitutively stimulate the generation of A beta in AD. Here we discovered that protopanaxadiol derivative 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopanaxadiol-3 beta-yl)-urea (DDPU) effectively improved the activity of daily living (ADL) and cognitive deficits in APP/PS1 transgenic mice. The crosstalk between A beta and ER stress has been intensively investigated by using DDPU as a probe. DDPU reduced A beta production mainly by inhibiting the PERK/eIF2 alpha signaling-mediated BACE1 translation and stimulated A beta clearance by promoting autophagy as a PI3K inhibitor through PI3K/AKT/mTOR signaling pathway, while exhibited neuroprotective effect involving attenuation of ER stress. DDPU might be the first reported ginsenoside derivative with dual effects on both autophagy promotion and ER stress amelioration. Our results have highlighted the potential of DDPU in the treatment of AD. (C) 2017 Elsevier Ltd. All rights reserved.
资助项目	National Natural Science Foundation of China[81220108025] ; National Natural Science Foundation of China[81473141] ; NSFC-TRF collaboration projects[81561148011] ; NSFC-TRF collaboration projects[DBG5980001] ; Drug Innovation Project of SIMM[CASIMM0120154035] ; Personalized Medicine-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of Chinese Academy of Sciences[XDA12040303] ; Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine)[17KJA350002] ; National Natural Science Foundation for Young Scientists of China[81703806] ; Natural Science Foundation for Young Scientists of Nanjing University of Chinese medicine[13XZR27]
WOS关键词	ENDOPLASMIC-RETICULUM STRESS ; UNFOLDED-PROTEIN RESPONSE ; AMELIORATES MEMORY IMPAIRMENT ; APPSWE/PS1 BIGENIC MODEL ; ALZHEIMERS-DISEASE ; AMYLOID-BETA ; PANAX-GINSENG ; RAT MODEL ; TRANSLATIONAL REGULATION ; TRIGGERED APOPTOSIS
WOS研究方向	Neurosciences & Neurology ; Pharmacology & Pharmacy
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000423655800009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279886]
专题	药理学第三研究室
通讯作者	Wang, Jiaying; Shen, Xu
作者单位	1.Nanjing Univ Chinese Med, Sch Med & Life Sci, State Key Lab Cultivat Base TCM Qual & Efficacy, Nanjing 210023, Jiangsu, Peoples R China; 2.Nanjing Univ Chinese Med, Key Lab Drug Target & Drug Degenerat Dis, Nanjing 210023, Jiangsu, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Guo, Xiaodan,Lv, Jianlu,Lu, Jian,et al. Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy[J]. NEUROPHARMACOLOGY,2018,130:77-91.
APA	Guo, Xiaodan.,Lv, Jianlu.,Lu, Jian.,Fan, Lei.,Huang, Xi.,...&Shen, Xu.(2018).Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy.NEUROPHARMACOLOGY,130,77-91.
MLA	Guo, Xiaodan,et al."Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy".NEUROPHARMACOLOGY 130(2018):77-91.