Inhibitor Kappa B Kinase β, Modulated by DJ-1/p-VHL, Reduces Phosphorylated Tau (p-Tau) Accumulation via Autophagy in Alzheimer's Disease Model
Inhibitor Kappa B Kinase β, Modulated by DJ-1/p-VHL, Reduces Phosphorylated Tau (p-Tau) Accumulation via Autophagy in Alzheimer's Disease Model
复制标题
DOI：
10.1016/j.neuroscience.2020.10.005
复制
发表时间：
2021-01-01
期刊：
影响因子：
3.3
通讯作者：
Liu, Xu
中科院分区：
文献类型：
--
作者：
Chen, Wei-Ping;Zhang, Ge;Liu, Xu
已经证明抑制剂κ B激酶β（IKK β）促进自噬，其进而介导p-Tau蛋白清除。然而，阿尔茨海默病（AD）的具体调控机制尚不清楚。首先，通过侧脑室（ICV）注射AD模型。淀粉样蛋白1-42（A β（1-42））肽。随后，向小鼠注射设计为靶向DJ-1或A β（1-42）或A β（1 - 42）+ shNC或A β（1 -42）+针对DJ-1的shRNA的shRNA腺病毒转导颗粒。将针对DJ-1的shRNA注射到小鼠的海马体中（每只小鼠8 × 10（4）病毒颗粒）连续7天。免疫组化法检测A β在小鼠海马的蓄积，HE染色法检测小鼠海马的病理改变。将sh-IKK β、shDJ-1、pcDNA-IKK β和pcDNA-DJ-1质粒转染HT-22细胞，MTT法检测细胞活力，TUNEL法检测细胞凋亡，Hoechst法检测细胞凋亡。Western blotting检测蛋白质相对表达量。结果表明，A β（1-42）抑制自噬，上调p-Tau蛋白表达，IKK β和DJ-1过表达均能挽救A β（1 - 42）抑制的自噬，下调A β（1 - 42）诱导的p-Tau蛋白表达，DJ-1通过p-VHL上调IKK β，进一步促进自噬，降低p-Tau蛋白表达; DJ-1敲低抑制自噬并上调p-Tau蛋白表达，导致小鼠行为延迟。总之，在AD疾病模型中，由DJ-1/p-VHL调节的IKK β通过自噬减少p-Tau积累。本研究可为AD的治疗提供理论依据。(C)2020年IBRO。由爱思唯尔有限公司出版。保留所有权利。
It has been demonstrated Inhibitor Kappa B Kinase beta (IKK beta) facilitates autophagy, which in turn mediates p-Tau protein clearance. However, the specific regulatory mechanism in Alzheimer's disease (AD) remains unclear. Firstly, AD model was generated by the intracerebroventricular (ICV) injection of the.-amyloid 1-42 (A beta(1-42)) peptide. Subsequently, mice were injected with shRNA adenoviral transduction particles designed to target DJ-1 or A beta(1-42) or A beta(1-42) + shNC or A beta(1-42) + shRNA against DJ-1. shRNA against DJ-1 were injected into hippocampus of mice (8 x 10(4) viral particles for each mice) for seven consecutive days. Immunohistochemistry was performed to detect the accumulation of A beta in the hippocampus of mice, and Hematoxylin-Eosin (HE) staining assay was carried to detect pathological changes in the hippocampus of mice. Further, sh-IKK beta, shDJ-1, pcDNA-IKK beta and pcDNA-DJ-1 plasmids were transfected into HT-22 cells, MTT assay, TUNEL staining and Hoechst staining were performed to detect cell viability and apoptosis, respectively. Western blotting was carried to measure the relative expression of proteins. Findings indicated that A beta(1-42) inhibited autophagy and up-regulated p-Tau protein expression; Overexpression of IKK beta and DJ-1 all rescued the autophagy inhibited by A beta(1-42) and down-regulated p-Tau protein expression induced by A beta(1-42); DJ-1 up-regulated IKK beta via p-VHL, further promoted autophagy and reduced the expression of p-Tau protein; DJ-1 knockdown inhibited autophagy and up-regulated p-Tau protein expression, resulting in delayed behavior in mice. In conclusion, IKK beta, modulated by DJ-1/p-VHL, reduces p-Tau accumulation via autophagy in AD's disease model. This study may provide theoretical basis for the treatment of AD. (C) 2020 IBRO. Published by Elsevier Ltd. All rights reserved.