Modulation of Aβ 16-22 aggregation by glucose

• Published in: Physical chemistry chemical physics : PCCP 2024-02, Vol.26 (6), p.538-544
• Main Authors: Jain, Meenal, Sahoo, Abhilash, Matysiak, Silvina
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - chemistry; Crosslinking; Glucose; Humans; Hyperglycemia; Molecular structure; Peptide Fragments - metabolism; Peptides; Protein Structure, Secondary; Self-assembly; Thermodynamics
• ISSN: 1463-9076; 1463-9084; 1463-9084
• DOI: 10.1039/d3cp04494g

The self-assembly of amyloid-beta (Aβ) peptides into fibrillar structures in the brain is a signature of Alzheimer's disease. Recent studies have reported correlations between Alzheimer's disease and type-2 diabetes. Structurally, hyperglycemia induces covalent protein crosslinkings by advanced glycation end products (AGE), which can affect the stability of Aβ oligomers. In this work, we leverage physics-based coarse-grained molecular simulations to probe alternate thermodynamic pathways that affect peptide aggregation propensities at varying concentrations of glucose molecules. Similar to previous experimental reports, our simulations show a glucose concentration-dependent increase in Aβ aggregation rates, without changes in the overall secondary structure content. We discovered that glucose molecules prefer partitioning onto the aggregate-water interface at a specific orientation, resulting in a loss of molecular rotational entropy. This effectively hastens the aggregation rates, as peptide self-assembly can reduce the available surface area for peptide-glucose interactions. This work introduces a new thermodynamic-driven pathway, beyond chemical cross-linking, that can modulate Aβ aggregation. Preferential orientation of glucose molecules decreases the rotational entropy aiding faster aggregation of amyloid-beta (Aβ) peptide fragments.