Alzheimer Aβ peptide interactions with lipid membranes: fibrils, oligomers and polymorphic amyloid channels

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biophysics

Background:

• Fibrillar aggregates of misfolded amyloid proteins are linked to neurodegenerative and metabolic diseases.
• Amyloid beta (Aβ) peptides in Alzheimer disease (AD) exert toxicity by disrupting cellular membrane function.
• Understanding Aβ-membrane interactions is crucial for elucidating disease mechanisms.

Purpose of the Study:

• To investigate the initial molecular mechanisms of amyloid beta (Aβ) interactions with lipid membranes.
• To identify the driving forces behind Aβ peptide insertion into the hydrophobic core of lipid bilayers.
• To explore the structural characteristics of amyloid aggregates when embedded within cell membranes.

Main Methods:

• Atomistic molecular dynamics (MD) simulations were employed.
• Simulations included Aβ 9-40 fibrillar oligomers, lipid bilayers, and explicit water molecules.
• Analysis focused on the initial stages of Aβ-membrane association.

Main Results:

• Electrostatic interactions between charged peptide residues and lipid headgroups are the primary drivers of Aβ penetration into membranes.
• The C-termini of amyloid fibrils/oligomers can insert into the hydrophobic membrane region.
• Amyloid structures within lipid bilayers exhibit polymorphic characteristics, including helical content in lipid-interacting regions.

Conclusions:

• Aβ-membrane interactions are initiated and modulated by electrostatic forces.
• These interactions can lead to the formation of amyloid ion channels with diverse structures.
• The findings provide insights into the molecular basis of Aβ toxicity and membrane disruption in diseases like AD.