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

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Alzheimer's disease (AD) progression is linked to beta-amyloid (Aβ) variants with diverse aggregation and toxicity.
• Gelsolin (GSN) is a potential regulator of Aβ dynamics, but its interaction mechanisms with Aβ isoforms are unclear.

Purpose of the Study:

• To systematically investigate GSN interaction dynamics with Aβ fragments of varying lengths.
• To characterize the structural determinants and binding kinetics of GSN-Aβ interactions.
• To establish a framework for developing stage-specific AD therapeutics.

Main Methods:

• Dual polarization interferometry was used to monitor binding kinetics and conformational changes.
• Simultaneous real-time measurement of adsorbed mass, layer thickness, and density.
• Computational docking simulations integrated with experimental data.

Main Results:

• GSN interactions with Aβ fragments exhibit a pronounced length-dependent mechanism.
• Binding kinetics and conformational changes were characterized across different Aβ lengths (Aβ1-42, Aβ1-40, Aβ9-37, Aβ1-16, Aβ1-11).
• Thermodynamic and structural complementarity relationships were elucidated.

Conclusions:

• GSN's interaction with Aβ is critically dependent on Aβ fragment length.
• Findings provide a theoretical basis for targeted AD therapeutic interventions.
• Enhanced understanding of molecular determinants in protein chaperone systems relevant to AD.