Protofibril-Fibril Interactions Inhibit Amyloid Fibril Assembly by Obstructing Secondary Nucleation

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Amyloid-β peptides (Aβ) form fibrils in Alzheimer's disease (AD) senile plaques.
• Metastable Aβ oligomers (AβO) may be the primary toxic species in AD.
• The interaction between Aβ protofibrils and fibrils is not well understood.

Purpose of the Study:

• To investigate the interplay between amyloid-β protofibrils and amyloid fibrils.
• To understand how protofibrils influence fibril assembly and toxicity.

Main Methods:

• Chemical kinetics
• Atomic force microscopy (AFM)
• Assembly studies using Aβ and lysozyme variants.

Main Results:

• Protofibrils bind to the lateral surfaces of amyloid fibrils.
• This interaction inhibits secondary nucleation and autocatalytic fibril proliferation.
• AβO antagonize fibril formation by competing for monomers and blocking nucleation sites.

Conclusions:

• Protofibril-fibril interactions are critical in governing the temporal evolution of amyloid species.
• These interactions influence the potential toxic activities of Aβ assemblies.
• Understanding this interplay is key to developing AD therapeutics.