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Toxic fibrillar oligomers of amyloid-β have cross-β structure

James C Stroud1, Cong Liu, Poh K Teng

  • 1Department of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, CA 90095, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 2, 2012
PubMed

Insights

Toxic amyloid-beta (Abeta42) fibrillar oligomers share cross-beta structures with amyloid fibrils. These oligomers form helical structures with a central pore, offering insights into Abeta

Area of Science:

  • Neuroscience
  • Biochemistry
  • Structural Biology

Background:

  • Amyloid fibers are implicated in neurodegenerative diseases.
  • Soluble oligomers of amyloid-forming proteins are considered the primary cytotoxic species.
  • Amyloid-beta (Abeta42) is a key protein implicated in Alzheimer's disease pathogenesis.

Purpose of the Study:

  • To characterize the structure and properties of toxic amyloid-beta (1-42) fibrillar oligomers (TABFOs).
  • To elucidate the molecular assembly of Abeta42 oligomers and their potential role in pore formation.
  • To provide a structural model consistent with observed properties of Abeta42 oligomers.

Main Methods:

  • Powder X-ray diffraction
  • Electron microscopy (EM)
  • Circular dichroism (CD) spectroscopy
  • Fourier-transform infrared (FTIR) spectroscopy
  • Chromatography
  • Conformational antibody binding assays
  • Cellular toxicity assays

Main Results:

  • TABFOs exhibit a cross-beta structure, similar to mature amyloid fibrils.
  • Abeta42 molecules in TABFOs form short protofilaments with helical beta-sheets that wrap into a superhelix.
  • The superhelix structure creates a central pore, suggesting a mechanism for Abeta-mediated pore formation.

Conclusions:

  • The proposed helical superhelix model explains key properties of Abeta42 fibrillar oligomers, including size heterogeneity, seeding ability, and morphology.
  • The identified pore structure offers insights into the cytotoxic mechanisms of amyloid oligomers in neurodegenerative diseases.
  • Understanding the structure of toxic oligomers is crucial for developing therapeutic strategies against amyloid diseases.

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