Conclusion
The findings of this study establish, for the first time, that these metabolites exert a neuroprotective activity by regulating intracellular proteolysis and confirm the role of autophagy and cathepsin B as possible targets of AD preventive/therapeutic strategies.
Results
Neuronal SH-SY5Y cells transfected with either the wild-type or the 717 valine-to-glycine amyloid precursor protein mutated gene are used as an AD model and treated with 5-(4'-hydroxyphenyl)-γ-valerolactone, 5-(3',4'-dihydroxyphenyl)-γ-valerolactone and 5-(3'-hydroxyphenyl)-γ-valerolactone-4'-sulfate. Combining in vitro and in silico studies, it is observed that the phenyl-γ-valerolactones of interest modulated cellular proteolysis via proteasome inhibition and consequent autophagy upregulation and inhibited cathepsin B activity, eventually reducing the amount of intra- and extracellular amyloid-beta (1-42) peptides.