Molecular insights into the primary nucleation of polymorphic amyloid β dimers in DOPC lipid bilayer membrane

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Alzheimer's disease (AD) is marked by cognitive decline and brain amyloid-beta (Aβ) plaques.
• Aβ oligomers, especially dimers, are considered toxic species that disrupt cell membranes.
• Understanding Aβ dimer interactions with membranes is crucial for AD pathogenesis.

Purpose of the Study:

• To investigate the impact of polymorphic Aβ dimers on 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membranes.
• To elucidate the role of Aβ dimer structure and N-termini domains in membrane interactions.
• To identify the driving forces behind Aβ dimer aggregation within lipid bilayers.

Main Methods:

• Computational modeling and simulations were used to study Aβ dimer interactions.
• Analysis of the effects of Aβ dimer conformation ('α-helix/random coil' vs. 'fibril-like') on DOPC membranes.
• Investigation of the role of specific amino acid residues (F19, F20) and N-termini domains in Aβ aggregation.

Main Results:

• DOPC membranes promote 'fibril-like' Aβ dimers while impeding 'α-helix/random coil' Aβ dimers.
• Aβ dimer N-termini domains influence aggregation within membrane environments.
• Aromatic π-π interactions involving F19 and F20 drive hydrophobic interactions and nucleation of Aβ dimers.
• Aβ dimers decrease DOPC membrane thickness and cause disruption due to extensive monomer-membrane contacts.

Conclusions:

• Polymorphic Aβ dimers exhibit distinct effects on DOPC membranes.
• Membrane-induced conformational changes and specific residue interactions are key in Aβ aggregation.
• This research provides molecular insights into early-stage Aβ dimer interactions with lipid bilayers, relevant to Alzheimer's disease.