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

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.

Keywords

• adeno-associated virus
• alzheimer’s disease
• app/ps1 mice
• carboxyl terminus of hsp70 interacting protein
• gene therapy