Miser-Salihoglu_2026_Molecules_31_

The triterpenoid and polysaccharide constituents of Ganoderma lucidum (GL) are believed to influence key pathogenic pathways in Alzheimer's disease (AD). This study first examined the molecular rationale for GL's neuroprotective properties by subjecting its principal triterpenoids, Ganoderic Acid A&B, to computational profiling. Molecular docking was performed against human acetylcholinesterase (AChE), TNF-alpha, COX-2, IL-6, caspase-3, Bcl-2, and the Keap1-Nrf2 complex using CB-Dock2, alongside SwissADME-based physicochemical and ProTox-3.0-based toxicological screening. These targeted pathways were then biologically validated in an in vitro AD model induced by Abeta(1-42) toxicity in SH-SY5Y cells, assessing AChE activity, apoptosis, ROS levels, mitochondrial membrane potential (MMP), and cytokine expression (COX-2, TGF-beta1, IL-6, TNF-alpha, IL-10). Docking revealed high binding affinities of both triterpenoids toward all seven targets (Vina scores: -7.3 to -10.4 kcal/mol), predicting strong modulation of cholinergic, inflammatory, apoptotic, and antioxidant pathways. Consistent with these predictions, GL extract significantly reduced TNF-alpha, COX-2, and IL-6 mRNA and protein levels, attenuated ROS accumulation, preserved MMP except at 500 microg/mL, and exerted a concentration-dependent antiapoptotic effect. IL-10 and TGF-beta1 showed complex, dose-dependent patterns, reflecting indirect regulatory responses. Together, these findings support GL's neuroprotective potential against Abeta-induced toxicity through direct engagement of cholinergic, inflammatory, apoptotic, and antioxidant regulatory proteins.