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Beta-amyloid 25 to 35 is intercalated in anionic and zwitterionic lipid membranes to different extents
Silvia Dante1, Thomas Hauss, Norbert A Dencher
1Physical Biochemistry, Darmstadt University of Technology, Petersenstrasse 22, D-64287 Darmstadt, Germany. silvia.dante@hmi.de
Abstract:
Neuronal plasma membranes are thought to be the primary target of the neurotoxic beta-amyloid peptides (Abeta) in the pathogenesis of the Alzheimer's disease. Histologically, Abeta peptides are observed as extracellular macroscopic senile plaques, and most biophysical techniques have indicated the presence of Abeta close to the lipid headgroup region but not in the core of the membrane bilayers. The focus of this study is an investigation of the interaction between Abeta and lipid bilayers from a structural point of view. Neutron diffraction with the use of selectively deuterated amino acids has allowed us to determine unambiguously the position of the neurotoxic fragment Abeta (25-35) in the membrane. Two populations of the peptide are detected, one in the aqueous vicinity of the membrane surface and the second inside the hydrophobic core of the lipid membrane. The location of the C terminus was studied in two different lipid compositions and was found to be dependent on the surface charge of the membrane. The localization of beta-amyloid peptides in cell membranes will offer new insights on their mechanism in the neurodegenerative process associated with Alzheimer's disease and might provide clues for therapeutic developments.
Insights
Neurotoxic beta-amyloid peptides (Abeta) interact with neuronal membranes in Alzheimer's disease. This study reveals Abeta peptides localize both on the membrane surface and within its hydrophobic core.
Area of Science:
- Neuroscience
- Biophysics
- Structural Biology
Background:
- Neuronal plasma membranes are implicated in Alzheimer's disease pathogenesis.
- Beta-amyloid peptides (Abeta) are neurotoxic and associated with senile plaques.
- Previous studies localized Abeta near lipid headgroups, not within the membrane core.
Purpose of the Study:
- To structurally investigate the interaction between Abeta peptides and lipid bilayers.
- To determine the precise location of the neurotoxic Abeta (25-35) fragment within membranes.
- To understand how membrane properties influence Abeta localization.
Main Methods:
- Neutron diffraction utilizing selectively deuterated amino acids.
- Structural analysis of Abeta (25-35) peptide.
- Investigation across two distinct lipid compositions.
Main Results:
- Two distinct populations of Abeta (25-35) were identified: one near the aqueous surface and another within the hydrophobic core.
- The C-terminal localization of Abeta was dependent on the membrane's surface charge.
- Specific positioning of Abeta within lipid bilayers was unambiguously determined.
Conclusions:
- Beta-amyloid peptides can penetrate the hydrophobic core of neuronal membranes.
- Understanding Abeta localization provides new insights into Alzheimer's disease mechanisms.
- Findings may guide the development of novel therapeutic strategies for Alzheimer's disease.