Length-Dependent Aβ-Gelsolin Interactions Regulate Amyloid Aggregation in Alzheimer’s Disease

The pathological involvement of β-amyloid (Aβ) protein variants in Alzheimer's disease (AD) progression manifests through distinct aggregation patterns, neurotoxic profiles, and spatial distributions contingent upon their polypeptide lengths. While gelsolin (GSN) has emerged as a potential regulatory factor in Aβ dynamics, the structural determinants governing its interaction with various Aβ isoforms remain poorly characterized. Building upon our previous demonstration of GSN-mediated inhibition of β-amyloid protein 1-42 (Aβ₁₋₄₂) fibrillogenesis through monomer binding, we present the first systematic investigation of GSN interaction dynamics with Aβ fragments of varying lengths (Aβ₁₋₄₂, Aβ₁₋₄₀, Aβ₉₋₃₇, Aβ₁₋₁₆, and Aβ₁₋₁₁) using dual polarization interferometry. Our experimental paradigm employed simultaneous real-time monitoring of three critical biophysical parameters (adsorbed mass, layer thickness, and density) for characterizing binding kinetics and conformational changes. This multiparametric analysis revealed a pronounced length-dependent mechanism underlying GSN-Aβ interactions. Through an integrated approach combining multiscale experimental dynamics with computational docking simulations, we elucidated the intricate relationship between interaction thermodynamics and structural complementarity. These findings established a theoretical framework for developing stage-specific therapeutic interventions in AD management while advancing our understanding of molecular determinants in protein chaperone systems.