Incensole Acetate Regulates the Sirtuin-Insulin Signaling Axis in an Experimental Alzheimer's Disease Model

Background/Objectives: Alzheimer's disease (AD) is associated with impaired brain insulin signaling, oxidative stress, and neuroinflammation. This study investigated the effects of incensole acetate (IA) on sirtuin-associated insulin-signaling and cellular stress-response pathways using integrated computational and in vitro approaches. Methods: ADMET prediction, molecular docking, molecular dynamics simulations, and MM-PBSA analyses were performed for IA against SIRT1, SIRT3, and SIRT6 and compared with their corresponding reference ligands. An Aβ1-42-induced AD model was established in mesenchymal stem cell-derived neurons. The effects of IA on insulin-signaling components, sirtuins, Aβ, NF-κB, NRF2, and PPARα were evaluated using RT-qPCR, Western blotting, and immunofluorescence. Results: IA showed weaker docking affinities than the corresponding reference ligands for all three sirtuins, whereas trajectory-based analyses revealed target-dependent dynamic behavior. MM-PBSA-derived binding-energy estimates were -35.16 ± 3.32, -30.24 ± 3.63, and -38.26 ± 3.90 kcal/mol for IA with SIRT1, SIRT3, and SIRT6, respectively, with IA showing a more favorable relative energetic profile than 8L9 for SIRT6. In vitro, IA treatment was associated with reduced detectable Aβ levels and modulation of INSR, IRS, AKT, and AS160 expression. IA increased SIRT1 and SIRT6 expression, whereas SIRT3 protein levels were not significantly altered. IA also reduced NF-κB and increased NRF2 and PPARα expression. Conclusions: IA modulated insulin-signaling-related, sirtuin-associated, inflammatory, oxidative-stress, and metabolic markers in an Aβ1-42-induced cellular AD model. Computational analyses support potential IA-sirtuin interactions, particularly a favorable relative MM-PBSA energetic profile for SIRT6; however, direct sirtuin activation or causal sirtuin-mediated signaling was not established.