Modulation of Aβ 16-22 aggregation by glucose.

Area of Science:

• Neuroscience
• Biophysics
• Computational Chemistry

Background:

• Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) fibril formation in the brain.
• Type-2 diabetes and hyperglycemia are increasingly linked to AD pathogenesis.
• Hyperglycemia can cause advanced glycation end products (AGEs), potentially altering Aβ stability.

Purpose of the Study:

• To investigate the thermodynamic mechanisms by which glucose influences Aβ peptide aggregation.
• To explore how varying glucose concentrations affect Aβ aggregation propensities using molecular simulations.

Main Methods:

• Physics-based coarse-grained molecular dynamics simulations were employed.
• Simulations probed aggregation pathways at different glucose concentrations.
• Analysis focused on peptide aggregation rates and glucose-peptide interactions.

Main Results:

• Simulations confirmed a glucose concentration-dependent increase in Aβ aggregation rates.
• No significant changes in Aβ secondary structure content were observed.
• Glucose molecules were found to preferentially bind to the aggregate-water interface, reducing molecular rotational entropy and accelerating aggregation.

Conclusions:

• Glucose can enhance Aβ aggregation through a thermodynamic pathway involving interfacial binding and entropy loss.
• This mechanism offers an alternative explanation for the link between hyperglycemia and Alzheimer's disease, beyond AGE cross-linking.