Investigation of the Effects of Acacetin on Autophagy Pathway and Exosome Release in Amyloid Beta Peptide-Induced Toxicity Models

Abstract

Understanding the mechanism behind Alzheimer's disease is imperative due to the critical role of the autophagy pathway in protein homeostasis and neuronal survival. Autophagy pathway irregularities in neurons may increase exosome-mediated toxic protein transport, which can spread neurodegenerative diseases. Compelling evidence hints that acacetin (ACA) is a naturally occurring biocomponent exhibiting neuroprotective pharmacological properties. However, further molecular investigations are pressing to uncover the therapeutic potential of ACA. The present investigation endeavors to scrutinize the impact of ACA on the autophagy pathway and exosome release in an amyloid beta (A beta) peptide-induced toxicity model. Herein, first, molecular modeling was performed between ACA and autophagy-related proteins. Afterward, the A beta peptide-induced toxicity model cells were treated with ACA, and total and exosomal protein isolation was carried out and analyzed. Considering the findings, our molecular dynamics simulation of the ACA-protein complexes, spanning 100 ns, conclusively demonstrated stable protein-ligand interactions. Additionally, ACA was determined to regulate LC3II, Beclin-1, p62, and Lamp2a protein levels and reduce amyloid-beta and Alix protein levels. In conclusion, our study highlights the significant in vitro neuroprotective effect of ACA against A beta toxicity through autophagy. Moving forward, future studies may seek to elucidate the specific neuroprotective, therapeutic effects and mechanisms of ACA via autophagy in in vivo models. Addressing the identified limitations and capitalizing on the outlined future prospects are essential steps towards harnessing the therapeutic potential of ACA in combating neurodegenerative diseases, offering renewed hope for patients and caregivers alike.