Multivariate effects of pH, salt, and Zn²⁺ ions on Aβ₄₀ fibrillation

Amyloid-β (Aβ) peptide aggregation plays a central role in the progress of Alzheimer's disease (AD), of which Aβ-deposited extracellular amyloid plaques are a major hallmark. The brain micro-environmental variation in AD patients, like local acidification, increased ionic strength, or changed metal ion levels, cooperatively modulates the aggregation of the Aβ peptides. Here, we investigate the multivariate effects of varied pH, ionic strength and Zn²⁺ on Aβ₄₀ fibrillation kinetics. Our results reveal that Aβ fibrillation kinetics are strongly affected by pH and ionic strength suggesting the importance of electrostatic interactions in regulating Aβ₄₀ fibrillation. More interestingly, the presence of Zn²⁺ ions can further alter or even reserve the role of pH and ionic strength on the amyloid fibril kinetics, suggesting the importance of amino acids like Histidine that can interact with Zn²⁺ ions. Both pH and ionic strength regulate the secondary nucleation processes, however regardless of pH and Zn²⁺ ions, ionic strength can also modulate the morphology of Aβ₄₀ aggregates. These multivariate effects in bulk solution provide insights into the correlation of pH-, ionic strength- or Zn²⁺ ions changes with amyloid deposits in AD brain and will deepen our understanding of the molecular pathology in the local brain microenvironment.