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紫锥菊苷通过靶向阿尔茨海默病小鼠模型中的内质网应激传感器PERK来抑制淀粉样蛋白生成并调节F-肌动蛋白重塑。

Echinacoside Suppresses Amyloidogenesis and Modulates F-actin Remodeling by Targeting the ER Stress Sensor PERK in a Mouse Model of Alzheimer's Disease.

作者信息

Dai Yuan, Han Guanghui, Xu Shijun, Yuan Yongna, Zhao Chunyan, Ma Tao

机构信息

Institute of Material Medica Integration and Transformation for Brain Disorders, Chengdu University of Traditional Chinese Medicine, Chengdu, China.

School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China.

出版信息

Front Cell Dev Biol. 2020 Nov 19;8:593659. doi: 10.3389/fcell.2020.593659. eCollection 2020.

DOI:10.3389/fcell.2020.593659
PMID:33330477
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7717986/
Abstract

Endoplasmic reticulum stress (ERS) plays a vital and pathogenic role in the onset and progression of Alzheimer's disease (AD). Phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) induced by ERS depresses the interaction between actin-binding protein filamin-A (FLNA) and PERK, which promotes F-actin accumulation and reduces ER-plasma membrane (PM) communication. Echinacoside (ECH), a pharmacologically active component purified from , exhibits multiple neuroprotective activities, but the effects of ECH on ERS and F-actin remodeling remain elusive. Here, we found ECH could inhibit the phosphorylation of PERK. Firstly ECH can promote PERK-FLNA combination and modulate F-actin remodeling. Secondly, ECH dramatically decreased cerebral Aβ production and accumulation by inhibiting the translation of BACE1, and significantly ameliorated memory impairment in 2 × Tg-AD mice. Furthermore, ECH exhibited high affinity to either mouse PERK or human PERK. These findings provide novel insights into the neuroprotective actions of ECH against AD, indicating that ECH is a potential therapeutic agent for halting and preventing the progression of AD.

摘要

内质网应激（ERS）在阿尔茨海默病（AD）的发生和发展中起着至关重要的致病作用。ERS诱导的蛋白激酶R样内质网激酶（PERK）磷酸化会抑制肌动蛋白结合蛋白细丝蛋白A（FLNA）与PERK之间的相互作用，这会促进F-肌动蛋白积累并减少内质网-质膜（PM）通讯。紫锥菊苷（ECH）是从[具体来源未给出]中纯化得到的一种具有药理活性的成分，具有多种神经保护活性，但ECH对ERS和F-肌动蛋白重塑的影响仍不清楚。在此，我们发现ECH可以抑制PERK的磷酸化。首先，ECH可以促进PERK-FLNA结合并调节F-肌动蛋白重塑。其次，ECH通过抑制β-分泌酶1（BACE1）的翻译显著降低大脑中淀粉样蛋白β（Aβ）的产生和积累，并显著改善2×Tg-AD小鼠的记忆障碍。此外，ECH对小鼠PERK或人PERK均表现出高亲和力。这些发现为ECH对AD的神经保护作用提供了新的见解，表明ECH是一种用于阻止和预防AD进展的潜在治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/91e8/7717986/5f0552ff47c5/fcell-08-593659-g010.jpg
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