Exploring the Protective Effects of Two Alkaloids 1 and 2 from Aspergillus terreus C23–3 on Neuronal Cells by Combining Bioinformatics Prediction and Experimental Verification

Alzheimer's disease (AD) is an irreversible neurodegenerative disease that can lead to brain cell death and brain atrophy, manifested as memory loss, cognitive decline, and behavioral abnormalities. Its mechanism is complex, and there is currently no effective treatment method. The search for new therapies and natural drug candidates has become the focus of research. In recent years, marine-derived strains of Aspergillus terreus have become an important research direction for treating AD due to the unique structure and biological activity of their secondary metabolites. In this study, we investigated the potential of two alkaloids from Aspergillus terreus C23-3 in the treatment of AD through bioinformatics analysis and experimental validation. Bioinformatics analyses showed that the two alkaloids may act by modulating key targets associated with AD, especially alkaloid 2, which may exert significant therapeutic effects on AD by inhibiting glycogen synthase kinase-3β (GSK-3β) activity and reducing the level of hyperphosphorylation of Tau proteins. Molecular docking experiments showed that alkaloids 1 and 2 formed stable complexes with GSK-3β with a high affinity. Cellular experiments showed that alkaloids 1 and 2 could effectively inhibit apoptosis and injury in HT-22 cells. Further studies showed that alkaloid 2 reduced the phosphorylation level of Tau protein and attenuated oxidative-stress-induced neurological injury by inhibiting GSK-3β and its related pathways. These results suggest that alkaloid 2 has significant potential for AD therapy.