Hu Zhengwei, Yang Jing, Zhang Shuo, Li Mengjie, Zuo Chunyan, Mao Chengyuan, Zhang Zhongxian, Tang Mibo, Shi Changhe, Xu Yuming
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan Province, China.
Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan Province, China.
Neural Regen Res. 2025 Jan 1;20(1):253-264. doi: 10.4103/NRR.NRR-D-23-01277. Epub 2024 Mar 1.
JOURNAL/nrgr/04.03/01300535-202501000-00033/figure1/v/2024-05-14T021156Z/r/image-tiff The E3 ubiquitin ligase, carboxyl terminus of heat shock protein 70 (Hsp70) interacting protein (CHIP), also functions as a co-chaperone and plays a crucial role in the protein quality control system. In this study, we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer's disease. We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain. CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests, reduced amyloid-β plaques, and decreased the expression of both amyloid-β and phosphorylated tau. CHIP also alleviated the concentration of microglia and astrocytes around plaques. In APP/PS1 mice of a younger age, CHIP overexpression promoted an increase in ADAM10 expression and inhibited β-site APP cleaving enzyme 1, insulin degrading enzyme, and neprilysin expression. Levels of HSP70 and HSP40, which have functional relevance to CHIP, were also increased. Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated, which may also reflect a potential mechanism for the neuroprotective effect of CHIP. Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice. Indeed, overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer's disease.
《期刊》/nrgr/04.03/01300535 - 202501000 - 00033/图1/v/2024 - 05 - 14T021156Z/r/图像 - tiff 热休克蛋白70（Hsp70）相互作用蛋白（CHIP）的羧基末端作为E3泛素连接酶，也作为一种共伴侣发挥作用，并在蛋白质质量控制系统中起关键作用。在本研究中，我们旨在探讨过表达CHIP对阿尔茨海默病的神经保护作用。我们使用了一种能够穿越血脑屏障的腺相关病毒载体，以介导APP/PS1小鼠脑中CHIP的过表达。CHIP过表达显著改善了APP/PS1小鼠在莫里斯水迷宫和筑巢试验中的表现，减少了淀粉样β斑块，并降低了淀粉样β和磷酸化tau的表达。CHIP还减轻了斑块周围小胶质细胞和星形胶质细胞的浓度。在年龄较小的APP/PS1小鼠中，CHIP过表达促进了ADAM10表达的增加，并抑制了β位点APP裂解酶1、胰岛素降解酶和中性内肽酶的表达。与CHIP具有功能相关性的HSP70和HSP4（此处原文可能有误，推测为HSP40）水平也有所增加。CHIP过表达小鼠海马体的单核转录组测序表明，溶酶体途径和少突胶质细胞相关的生物学过程上调，这也可能反映了CHIP神经保护作用的潜在机制。我们的研究表明，CHIP有效地减轻了APP/PS1小鼠的行为和病理表现。事实上，CHIP的过表达可能是治疗阿尔茨海默病的一种有益方法。
