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Aβ42 fibril formation from predominantly oligomeric samples suggests a link between oligomer heterogeneity and fibril

Christine Xue1, Joyce Tran1, Hongsu Wang1

  • 1Department of Neurology, Brain Research Institute, Molecular Biology Institute, University of California, 710 Westwood Plaza, Los Angeles, CA 90095, USA.

Royal Society Open Science
|August 17, 2019
PubMed

Insights

Alzheimer's disease involves amyloid-β (Aβ) oligomers. Smaller Aβ42 oligomers aggregate into fibrils faster than larger ones, suggesting a link between oligomer size and Alzheimer's disease progression.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Amyloid-β (Aβ) oligomers are central to Alzheimer's disease pathogenesis.
  • Understanding the role of diverse Aβ oligomer sizes in aggregation and fibrillization remains incomplete.

Purpose of the Study:

  • To investigate the relationship between Aβ42 oligomer size heterogeneity and subsequent fibril formation kinetics.
  • To explore how oligomer size influences the structural properties and solubilization of resulting amyloid fibrils.

Main Methods:

  • Fractionation of Aβ42 oligomers using ultrafiltration.
  • Monitoring fibril formation kinetics (lag time and growth rate) at 37°C.
  • Assessing fibril solubilization using epigallocatechin gallate.

Main Results:

  • Aβ42 spontaneously forms a heterogeneous mixture of oligomers.
  • Smaller oligomer fractions exhibited faster fibril formation rates (shorter lag time, faster growth) compared to larger oligomer fractions.
  • Fibrils derived from larger oligomers were more susceptible to epigallocatechin gallate-induced solubilization, suggesting structural differences.

Conclusions:

  • Oligomer size heterogeneity in Aβ42 samples influences fibril formation kinetics.
  • Distinct Aβ oligomer sizes may lead to structurally different amyloid fibrils, contributing to fibril polymorphism in Alzheimer's disease.
Keywords:
Alzheimer diseaseaggregation kineticsamyloidneurodegenerationoligomerization

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