Transmembrane structures for Alzheimer's Aβ(1-42) oligomers
Birgit Strodel1, Jason W L Lee, Christopher S Whittleston
1Institut für Strukturbiologie und Biophysik, Strukturbiochemie, Forschungszentrum Jülich, 52425 Jülich, Germany. b.strodel@fz-juelich.de
Journal of the American Chemical Society
|September 9, 2010
Summary
Alzheimer's amyloid beta-peptide (Aβ) oligomers form pores in membranes. Stable Aβ(1-42) structures suggest tetrameric and hexameric β-sheet subunits may form these toxic pores.
Area of Science:
- Biophysics
- Computational Chemistry
- Neuroscience
Background:
- Alzheimer's disease is linked to amyloid beta-peptide (Aβ) oligomers.
- Aβ oligomers are hypothesized to cause neuronal toxicity via membrane pore formation.
Purpose of the Study:
- To model Aβ(1-42) oligomers in a membrane environment.
- To elucidate the structural basis of Aβ-induced membrane disruption and toxicity.
Main Methods:
- Basin-hopping global optimization for structure identification.
- Introduction of a parallel tempering scheme and oligomer generation procedure.
- Modeling Aβ(1-42) monomer and oligomers (up to octamer) in an implicit lipid bilayer.
Main Results:
- Identified a stable, membrane-spanning β-sheet structure for the Aβ(1-42) monomer.
- Observed ordered β-sheet structures for dimers to hexamers.
- Found that octamers dissociate into distinct, stabilized tetrameric units within the membrane.
Conclusions:
- Aβ pores may be composed of tetrameric and hexameric β-sheet subunits.
- Proposed Aβ pore models align with experimental biophysical and biochemical data.
- Provides structural insights into the mechanism of Alzheimer's amyloid toxicity.
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