AI Article Synopsis

  • Alzheimer's disease is primarily caused by amyloid-β (Aβ) peptides misfolding and forming aggregates that disrupt cell membranes, but the exact mechanism of this interaction remains unclear.
  • In this study, simulations over 120 microseconds explored how Aβ fibrils (in trimeric or hexameric forms) interact with various types of lipid bilayers, revealing that Aβ fibrils can bind more effectively to membranes with higher cholesterol content.
  • Key hydrophobic amino acid clusters and lysine residues were identified as critical for Aβ fibrils' stable interaction with cholesterol-rich membranes, suggesting potential targets for drug design to inhibit these harmful interactions.

Article Abstract

Alzheimer's disease is the most common form of dementia. Its aetiology is characterized by the misfolding and aggregation of amyloid-β (Aβ) peptides into β-sheet-rich Aβ oligomers/fibrils. Although multiple experimental studies have suggested that Aβ oligomers/fibrils interact with the cell membranes and perturb their structures and dynamics, the molecular mechanism of this interaction is still not fully understood. In the present work, we have performed a total of 120 μs-long simulations to investigate the interaction between trimeric or hexameric Aβ fibrils with either a 100% DPPC bilayer, a 70% DPPC-30% cholesterol bilayer or a 50% DPPC-50% cholesterol bilayer. Our simulation data capture the spontaneous binding of the aqueous Aβ fibrils with the membranes and show that the central hydrophobic amino acid cluster, the lysine residue adjacent to it and the C-terminal hydrophobic residues are all involved in the process. Moreover, our data show that while the Aβ fibril does not bind to the 100% DPPC bilayer, its binding affinity for the membrane increases with the amount of cholesterol. Overall, our data suggest that two clusters of hydrophobic residues and one lysine help Aβ fibrils establish stable interactions with a cholesterol-rich DPPC bilayer. These residues are likely to represent potential target regions for the design of inhibitors, thus opening new avenues in structure-based drug design against Aβ oligomer/fibril-membrane interaction.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10151222PMC
http://dx.doi.org/10.1016/j.csbj.2023.04.013DOI Listing

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