Abstract
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by metabolic dysregulation, oxidative stress, amyloid-β (Aβ) aggregation, metal dyshomeostasis, and mitochondrial dysfunction. Current treatments provide only symptomatic relief, highlighting the need for novel therapeutic strategies. This study investigates the metabolic effects of the alkaloids galantamine (GAL) and lycorine (LYC) in differentiated SH-SY5Y neuroblastoma cells, an established in vitro model for AD, which acquire a neuronal phenotype upon differentiation. Using untargeted and targeted NMR-based metabolomics combined with multivariate statistical analysis, we analyzed extracellular metabolic profiles under basal conditions and following Aβ42 exposure, both in the presence and absence of GAL and LYC. Our findings reveal distinct metabolic responses to Aβ toxicity, with significant alterations in pyruvate and glutamine metabolism. Both GAL and LYC contributed to the restoration of glutamine and lysine homeostasis, but LYC had a more pronounced effect, better sustaining cellular energy balance and mitochondrial function. Unlike LYC, GAL treatment was associated with pyruvate accumulation, highlighting a distinct metabolic response between the two compounds. These variations may reflect distinct mechanisms of action, potentially influencing their therapeutic roles in counteracting Aβ-induced toxicity. This study highlights the value of metabolic profiling for assessing neuroprotective agents and reinforces the potential of natural alkaloids in this context.