Can local heating and molecular crowders disintegrate amyloid aggregates?

Area of Science:

• Biophysics
• Computational Chemistry
• Neuroscience

Background:

• Alzheimer's disease is linked to amyloid-beta (Aβ) aggregate formation.
• Understanding Aβ aggregate disintegration is crucial for developing therapeutic strategies.

Purpose of the Study:

• To investigate the disintegration mechanism of a mature Aβ octamer.
• To explore the effects of local heating and crowding agents on Aβ disintegration.
• To propose a theoretical model for Aβ aggregation and disintegration kinetics.

Main Methods:

• Molecular dynamics simulations, including well-tempered metadynamics.
• Investigating local heating effects on Aβ segments.
• Varying sodium dodecyl sulphate (SDS) concentration to simulate crowding effects.
• Developing a novel two-state mean-field model.

Main Results:

• Aβ aggregates resist complete disintegration under local heating due to rapid thermal dissipation.
• High SDS concentrations inhibit aggregation but do not fully disintegrate existing aggregates.
• A multi-step Aβ octamer disintegration mechanism was revealed: octamer → pentamer/hexamer ⇌ tetramer → monomer.
• A rate-determining barrier of 45 kJ mol^-1 was identified for the octamer to pentamer/hexamer transition.
• The mean-field model provides insights into Aβ growth and disintegration kinetics.

Conclusions:

• Complete disintegration of Aβ aggregates is challenging due to high energy barriers.
• The study elucidates a detailed Aβ octamer disintegration pathway.
• The developed mean-field model offers a theoretical framework for understanding Aβ aggregation dynamics.
• Findings guide the development of novel strategies to combat Alzheimer's disease by targeting Aβ aggregates.