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Cryo-EM structures of amyloid-β 42 filaments from human brains

Yang Yang1, Diana Arseni1, Wenjuan Zhang1

  • 1Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.

Science (New York, N.Y.)
|January 13, 2022
PubMed

Insights

Alzheimer's disease involves amyloid-beta 42 (Aβ42) filament assembly. Researchers determined the cryo-EM structures of Aβ42 filaments from human brains, revealing two distinct types crucial for disease understanding.

Area of Science:

  • Neuroscience
  • Structural Biology
  • Biochemistry

Background:

  • Amyloid-beta 42 (Aβ42) peptide aggregation into filaments is a hallmark of Alzheimer's disease pathogenesis.
  • Understanding the structural variations of these filaments is critical for developing targeted therapies.

Purpose of the Study:

  • To determine the high-resolution structures of Aβ42 filaments directly from human brain tissue.
  • To compare brain-derived Aβ42 filament structures with those formed in vitro and in animal models.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to visualize Aβ42 filament structures.
  • Analysis of Aβ42 deposits from human brains of individuals with sporadic and familial Alzheimer's disease.
  • Examination of Aβ42 deposits in AppNL-F knock-in mouse models.

Main Results:

  • Two distinct, S-shaped protofilament folds were identified, forming two types of Aβ42 filaments.
  • Type I filaments were predominantly observed in sporadic Alzheimer's disease brains.
  • Type II filaments were found in familial Alzheimer's disease and other conditions, and also in AppNL-F mice.

Conclusions:

  • Human brain Aβ42 filament structures differ significantly from those assembled in vitro.
  • The identified filament types correlate with different forms of Alzheimer's disease and are recapitulated in a relevant mouse model.
  • These structural insights are vital for designing Aβ42 assembly inhibitors and advanced imaging agents for Alzheimer's disease.

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