Osthole's capacity to prevent tau aggregation, a key protein in tauopathy and Alzheimer's disease.

Aggregated forms of protein arising from misfolded variants under physiological conditions can lead to the development of disorders related to proteinopathy, including Alzheimer's disease (AD). Some small molecules derived from plants can enhance the process of protein disaggregation via various pathways. Among the different bioactive substances, osthole-a natural coumarin compound-can be highly effective against protein aggregation and associated proteinopathies. In this research, we investigated osthole's capacity to prevent tau aggregation, a key protein in tauopathy and AD. Osthole was discovered to impede amyloid fibril formation by modulating the kinetics of fibril assembly. In addition, osthole has the potential to enhance the α-helix percentage of tau, while the fractions of β-sheet and random coil were reduced, suggesting that osthole can proficiently stabilize tau structure. Osthole hindered the structural shift from random coil to β-sheet and the creation of hydrophobic areas. Fluorescence spectroscopy and docking analysis indicated that nonpolar and intermolecular energies play a greater role in forming the osthole-tau complex than polar energy, and hydrophobic residues LEU344, ILE354, and PHE346 participating in the strong interaction (logKb values ranging from 5.09 to 5.41 across the studied temperature range). Osthole effectively reduced amyloid-induced neurotoxicity in SH-SY5Y cells by inhibiting ROS production and caspase-3 mRNA expression and activity. In summary, we suggest that osthole could serve as a small molecule for treating different tauopathy-related disorders, justifying additional research moving forward.