Effects of treadmill exercise on endoplasmic reticulum protein folding and endoplasmic reticulum-associated protein degradation pathways in APP/PS1 mice

Abstract

A hallmark of Alzheimer's disease (AD) is the disruption of protein homeostasis (proteostasis), manifested by the misfolding and aggregation of proteins. Molecular chaperones and the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway in the ER are essential for correct protein folding and degradation of misfolded proteins respectively, thus contributing to the maintenance of proteostasis. The present study aimed to investigate whether the beneficial effects of exercise in an AD mice model is associated with changes in ER protein folding and ERAD. APP/PS1 transgenic and wild-type mice were subjected to treadmill exercise for three months. The levels of molecular chaperones, specifically protein disulfide isomerases (PDIs) and heat shock proteins (HSPs), as well as ERAD-associated molecules were analyzed in the hippocampus. The result revealed a decrease in mRNA levels of PDIA2, PDIA3, PDIA4, PDIA5, PDIA6, HSPA1B, HSPA8, HSP90B1, DNAJB2, CRYAB, and CNX, an increase in mRNA levels of HSPA5 and HSPH1, an increase in protein levels of HERPUD1, and a decrease in protein levels of VCP in APP/PS1 mice. However, following a 3-month treadmill exercise regimen, an increase in mRNA levels of PDIA2, PDIA4, PDIA6, HSPA1A, HSPA8, HSP90AB1, and DNAJB2, as well as an increase in protein levels of VCP and DERL2, and a decrease in protein levels of HERPUD1 were noted. Overall, our findings indicate that disruptions in hippocampal ER protein folding and ERAD pathways may be implicated in AD, with exercise serving as a regulator of these pathways.