Real-time analysis of the biomolecular interaction between gelsolin and Aβ 1-42 monomer and its implication for Alzheimer's disease.

Biomolecular interaction acts a pivotal part in understanding the mechanisms underlying the development of Alzheimer's disease (AD). Herein, we built a biosensing platform to explore the interaction between gelsolin (GSN) and different β-amyloid protein 1-42 (Aβ _1-42 ) species, including Aβ _1-42 monomer (m-Aβ), Aβ _1-42 oligomers with both low and high levels of aggregation (LLo-Aβ and HLo-Aβ) via dual polarization interferometry (DPI). Real-time molecular interaction process and kinetic analysis showed that m-Aβ had the strongest affinity and specificity with GSN compared with LLo-Aβ and HLo-Aβ. The impact of GSN on inhibiting aggregation of Aβ _1-42 and solubilizing Aβ _1-42 aggregates was evaluated by circular dichroism (CD) spectroscopy. The maintenance of random coil structure of m-Aβ and the reversal of β-sheet structure in HLo-Aβ were observed, demonstrating the beneficial effects of GSN on preventing Aβ from aggregation. In addition, the structure of m-Aβ/GSN complex was analyzed in detail by molecular dynamics (MD) simulation and molecular docking. The specific binding sites and crucial intermolecular forces were identified, which are believed to stabilize m-Aβ in its soluble state and to inhibit the fibrilization of Aβ _1-42 . Combined theoretical simulations and experiment results, we speculate that the success of GSN sequestration mechanism and the balance of GSN levels in cerebrospinal fluid and plasma of AD subjects may contribute to a delay in AD progression. This research not only unveils the molecular basis of the interaction between GSN and Aβ _1-42 , but also provides clues to understanding the crucial functions of GSN in AD and drives the development of AD drugs and therapeutic approaches.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024. Published by Elsevier B.V.)