Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (1): 253-264.doi: 10.4103/NRR.NRR-D-23-01277

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AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice

Zhengwei Hu1, 2, #, Jing Yang1, 3, 4, 5, #, Shuo Zhang1, 2, Mengjie Li1, Chunyan Zuo1, Chengyuan Mao1, 3, 4, 5, Zhongxian Zhang6, Mibo Tang7, Changhe Shi1, 3, 4, 5, *, Yuming Xu1, 3, 4, 5, *   

  1. 1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan Province, China; 2Academy of Medical Sciences of Zhengzhou University, Zhengzhou, Henan Province, China; 3NHC Key Laboratory of Prevention and treatment of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan Province, China; 4Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan Province, China; 5Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan Province, China; 6Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China; 7Department of Gerontology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan Province, China
  • Online:2025-01-15 Published:2025-01-15
  • Contact: Yuming Xu, MD, PhD, xuyuming@zzu.edu.cn; Changhe Shi, MD, PhD, shichanghe@gmail.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 91849115 and U1904207 (to YX), 81974211 and 82171247 (to CS); and Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences, No. 2020-PT310-01 (to YX).

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Abstract: 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.

Key words: adeno-associated virus, Alzheimer’s disease, APP/PS1 mice, carboxyl terminus of Hsp70 interacting protein, gene therapy