α-Asarone Maintains Protein Homeostasis Through SKN-1-Mediated Proteasome and Autophagy Pathways to Mitigate Aβ-Associated Toxicity in Caenorhabditis elegans

<i>Acorus tatarinowii</i> Schott (<i>A. tatarinowii</i>), a traditional Chinese medicine, has been widely used in the treatment of dementia, particularly AD. α-Asarone is the main active component of <i>A. tatarinowii</i> oil, and its neuroprotective effects and underlying molecular mechanism in AD remain unclear. In this study, we utilized different transgenic <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) AD models to investigate the neuroprotective mechanism of α-asarone in vivo. Our findings revealed that α-asarone significantly ameliorated Aβ- and tau-induced phenotypic abnormalities, including deficits in chemotaxis-related learning, hyposensitivity to exogenous serotonin, and impaired neuronal integrity. Furthermore, the α-asarone treatment effectively reduced Aβ-induced oxidative stress. Mechanistically, α-asarone reduced Aβ accumulation and maintained protein homeostasis by stimulating proteasome degradation and autophagy in an SKN-1/Nrf2-dependent manner. Our study highlights the potential of α-asarone as an SKN-1/Nrf2 activator and its capability to facilitate proteostasis, supporting its therapeutic potential for AD treatment.