Interprotofilament interactions between Alzheimer's Abeta1-42 peptides in amyloid fibrils revealed by cryoEM

Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4653-8. doi: 10.1073/pnas.0901085106. Epub 2009 Mar 5.


Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid plaques in the brain. This amyloid primarily contains amyloid-beta (Abeta), a 39- to 43-aa peptide derived from the proteolytic cleavage of the endogenous amyloid precursor protein. The 42-residue-length Abeta peptide (Abeta(1-42)), the most abundant Abeta peptide found in plaques, has a much greater propensity to self-aggregate into fibrils than the other peptides and is believed to be more pathogenic. Synthetic human Abeta(1-42) peptides self-aggregate into stable but poorly-ordered helical filaments. We determined their structure to approximately 10-A resolution by using cryoEM and the iterative real-space reconstruction method. This structure reveals 2 protofilaments winding around a hollow core. Previous hairpin-like NMR models for Abeta(17-42) fit well in the cryoEM density map and reveal that the juxtaposed protofilaments are joined via the N terminus of the peptide from 1 protofilament connecting to the loop region of the peptide in the opposite protofilament. This model of mature Abeta(1-42) fibrils is markedly different from previous cryoEM models of Abeta(1-40) fibrils. In our model, the C terminus of Abeta forms the inside wall of the hollow core, which is supported by partial proteolysis analysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid / metabolism*
  • Amyloid / ultrastructure*
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / ultrastructure*
  • Cryoelectron Microscopy
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism*
  • Peptide Fragments / ultrastructure*
  • Peptides / metabolism*
  • Protein Processing, Post-Translational
  • Static Electricity


  • Amyloid
  • Amyloid beta-Peptides
  • Peptide Fragments
  • Peptides
  • amyloid beta-protein (1-42)