Using the Aβ transgenic nematode strain CL2006 as a model, researchers in Chang Chen's group added LBE to the nematode food E. coli OP50 at a certain concentration during the larval L4 period to investigate the functional and molecular mechanisms of LBE in toxic Aβ production and clearance. LBE was found to significantly reduce the aggregation of Aβ and thus alleviate the muscle paralysis phenotype of CL2006 nematodes. On the one hand, LBE has strong antioxidant activity and can inhibit the production and aggregation of Aβ by activating the SKN-1 pathway to inhibit the production of excess ROS (Reactive oxygen species). On the other hand, LBE can activate the mitochondrial unfolded protein response (mtUPR) in CL2006 nematodes. Interfering with the expression of key mtUPR genes reverses the LBE-mediated decrease in Aβ levels and improves the nematode muscle paralysis phenotype. However, interfering with the expression of key genes in other protein degradation-related pathways, such as the proteasome system, the autophagic pathway and the endoplasmic reticulum unfolded protein response (ERUPR), did not inhibit the LBE-induced decrease in Aβ levels. Moreover, interference with the expression of the G protein-coupled receptor gene FSHR-1 inhibited the activation of mtUPR by LBE. Thus, LBE inhibits Aβ aggregation and maintains protein homeostasis through FSHR-1-mediated activation of mtUPR, thereby preventing further mitochondrial damage.
This study identifies for the first time that LBE exerts a protective effect on AD model nematodes through activation of the mitochondrial UPR, providing a new mechanism to reveal the important efficacy of LBP in the prevention and treatment of AD. Unlike previous studies on UPR in AD which have mostly focused on the endoplasmic reticulum UPR, this study provides new evidence for the cytoprotective role of mitochondrial UPR in the course of AD. Furthermore, many different neurodegenerative diseases may share a common cause and pathological mechanism - protein misfolding and aggregation. Therefore, this study also provides a new reference for the prevention and treatment of neurodegenerative diseases by enhancing the mitochondrial UPR.
