Alzheimer's Protective Cross-Interaction between Wild-Type and A2T Variants Alters Aβ₄₂ Dimer Structure

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Alzheimer's disease (AD) is a neurodegenerative disorder.
• Amyloid-beta (Aβ) dimers are the smallest known neurotoxic species implicated in AD.
• A single A2T mutation in heterozygous carriers shows a protective effect against AD.

Purpose of the Study:

• To investigate the structural impact of the A2T mutation on wild-type (WT) and A2T Aβ1-42 heterodimers.
• To understand the cross-interaction between WT and A2T variants in Aβ dimers.
• To explore the molecular mechanisms behind the protective effect of the A2T mutation in AD.

Main Methods:

• Atomistic replica exchange molecular dynamics (MD) simulations.
• Simulations of solvated WT homo- and A2T hetero- Aβ1-42 dimers.
• Total sampling of 51 μs for each system.

Main Results:

• Heterodimers showed weakened intrachain contacts between central and C-terminal hydrophobic residues.
• Many heterodimers lacked significant secondary structure and had weak interchain interfaces.
• The A2T N-terminus (residue F4) engaged in atypical interactions, leading to hydrophobic burial and potentially interfering with Aβ aggregation.

Conclusions:

• The A2T mutation alters Aβ1-42 heterodimer structure.
• Atypical N-terminus interactions in A2T heterodimers may inhibit toxic Aβ aggregation.
• These findings offer molecular insights into the protective effect of the A2T mutation against Alzheimer's disease.