Structural convergence and membrane interactions of Aβ_1-42 along the primary nucleation process studied by solid...

Area of Science:

• Biochemistry and Molecular Biology
• Neuroscience
• Biophysics

Background:

• Amyloidogenic aggregation of beta-amyloid (Aβ) peptides, particularly Aβ1-42, is implicated in Alzheimer's disease (AD) pathogenesis via cellular membrane disruption.
• Understanding the structural dynamics and membrane interactions of early Aβ aggregation intermediates is crucial but challenging due to their transient nature and heterogeneity.
• Aβ1-42 is known to be more cytotoxic and fibrillogenic than Aβ1-40, but the precise molecular mechanisms underlying this difference, especially concerning membrane interactions, remain unclear.

Purpose of the Study:

• To systematically investigate the molecular interactions of membrane-associated Aβ1-42 peptides during the primary nucleation phase of fibrillation.
• To elucidate the structural differences in membrane association and early aggregation between Aβ1-42 and Aβ1-40.
• To provide a molecular-level understanding of Aβ1-42's membrane-disrupting intermediates and explain its heightened cytotoxicity.

Main Methods:

• Solid-state nuclear magnetic resonance (ssNMR) spectroscopy was employed to study membrane-associated Aβ1-42 peptides.
• Dynamic Nuclear Polarization (DNP) enhanced ssNMR was utilized to improve sensitivity and probe local secondary structure and tertiary contacts.
• Comparative analysis was performed between Aβ1-42 and Aβ1-40 peptides in membrane-mimicking environments.

Main Results:

• Aβ1-42 forms smaller oligomers with a higher proportion of lipid-proximal peptides compared to Aβ1-40.
• Aβ1-42 exhibits more extensive residue-specific contacts with phospholipid headgroups across its sequence than Aβ1-40.
• In Aβ1-42, the segments involved in inter-strand assembly overlap with lipid-interacting segments, unlike in Aβ1-40; DNP-ssNMR confirmed early structural convergence and tertiary contacts in Aβ1-42 nucleation.

Conclusions:

• The study provides a detailed molecular understanding of Aβ1-42 nucleation and membrane interaction mechanisms.
• The observed differences in membrane association and early structural assembly between Aβ1-42 and Aβ1-40 directly explain the higher membrane-disrupting cytotoxicity of Aβ1-42.
• These findings offer critical insights into Alzheimer's disease pathogenesis at the molecular and membrane level.