Amyloid-beta Degradation and Neuroprotection of Dauricine Mediated by Unfolded Protein Response in a Caenorhabditis elegans Model of Alzheimer's disease

被引：21

作者：

Pu, Zhijun ^{[1
]}

Ma, Shuo ^{[1
]}

Wang, Lingfeng ^{[1
]}

Li, Mingxin ^{[1
]}

Shang, Lei ^{[2
]}

Luo, Yunfeng ^{[2
]}

Chen, Wei ^{[3
]}

机构：

[1] Guilin Med Univ, Guilin, Guangxi, Peoples R China

[2] Nanchang Univ, Jiangxi Res Inst Ophthalmol & Visual Sci, Affiliated Eye Hosp, Nanchang, Jiangxi, Peoples R China

[3] Guilin Med Univ, Affiliated Hosp, 109 North 2nd Huan Cheng Rd, Guilin 541004, Guangxi, Peoples R China

来源：

NEUROSCIENCE | 2018年 / 392卷

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

dauricine; unfolded protein response; ER-associated degradation; A beta; Alzheimer's disease; A-BETA(1-42) SECRETION; CASCADE HYPOTHESIS; HUMAN CELL; PROTEOSTASIS; PATHOGENESIS; CLEARANCE; TOXICITY; PATHWAY; EDEM; ACCUMULATION;

D O I：

10.1016/j.neuroscience.2018.09.022

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Amyloid plaque is a prominent pathologic hallmark in the brains of patients with Alzheimer's disease (AD), and it has been shown to be associated with endoplasmic reticulum (ER) stress response. However the precise regulation mechanism of amyloid-beta (A beta) toxicity remains unclear. Here, we found that dauricine could activate X-box binding protein 1 (XBP-1; active form XBP-1S) and eukaryotic translation initiation factor eIF2 alpha and thus delay the progression of AD in the A beta(1-42)-transgenic Caenorhabditis elegans CL2120. The ER stress response factor XBP-1 can be activated and shows neuroprotective activity through acceleration of An clearance. Our study reveals that dauricine activates the ire-1 ixbp-1 and perk/e/IF2 alpha pathways of the unfolded protein response, attenuates translation, and enhances ER-associated degradation, which reduces A beta expression and attenuates An-associated toxicity. On the contrary, xbp-1 depletion counteracts the effects of dauricine on Apassociated toxicity. These results underscore the functional relevance of XBP-1 in An toxicity and degradation, and highlight the potentially pharmacodynamic value of dauricine in preventing the progression of AD. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

引用

页码：25 / 37

页数：13