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Effects of applied surface-tension on membrane-assisted Aβ aggregation
Abhilash Sahoo1, Silvina Matysiak1,2
1Biophysics Program, Institute of Physical Science and Technology, University of Maryland, College Park, MD, USA.
Physical Chemistry Chemical Physics : PCCP
|September 13, 2021
Summary
Increased membrane curvature accelerates amyloid-beta (Aβ) peptide aggregation, a key step in Alzheimer's disease. Simulations reveal curved membranes promote Aβ fibril formation by increasing lipid packing defects and peptide diffusion.
Area of Science:
- Biophysics
- Computational Biology
- Neuroscience
Background:
- Amyloid-beta (Aβ) aggregate formation on cellular membranes is central to Alzheimer's disease pathogenesis.
- Experimental and computational studies face challenges in characterizing the biophysical mechanisms linking membrane properties and Aβ aggregation.
- A direct mechanistic link between membrane curvature and the rate of Aβ aggregation is currently lacking.
Purpose of the Study:
- To investigate the relationship between membrane curvature and the aggregation of a model amyloid-beta (Aβ) peptide (Aβ 16-22).
- To provide a mechanistic explanation for the observed correlation between increased membrane curvature and accelerated Aβ aggregation.
- To elucidate the effects of Aβ aggregation on the structure and organization of biological membranes.
Main Methods:
- Utilized molecular simulations employing a physics-based coarse-grained model.
- Simulated the aggregation of a model Aβ 16-22 peptide on membranes with varying degrees of curvature.
- Analyzed lipid packing defects, peptide diffusion rates, and membrane structural changes.
Main Results:
- Confirmed a positive correlation between increased membrane curvature and accelerated Aβ peptide aggregation, consistent with experimental findings.
- Identified that more curved membranes exhibit higher lipid packing defects, which facilitate hydrophobic interactions with Aβ peptides and enhance diffusion.
- Observed that interfacial Aβ aggregation induces heterogeneous headgroup-peptide interactions and a crowding effect, leading to a more ordered lipid headgroup region and disordered lipid tails.
Conclusions:
- Membrane curvature is a critical factor influencing the kinetics and morphology of Aβ aggregation.
- Lipid packing defects and enhanced peptide diffusion on curved membranes mechanistically explain faster Aβ aggregation.
- Aβ aggregation significantly alters membrane organization, impacting both lipid headgroups and tails, offering a comprehensive view of the biomembrane-peptide interplay.
