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Abstract 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 Zn 2+ on Aβ 40 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 Aβ 40 fibrillation. More interestingly, the presence of Zn 2+ 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 Zn 2+ ions. Both pH and ionic strength regulate the secondary nucleation processes, however regardless of pH and Zn 2+ ions, ionic strength can also modulate the morphology of Aβ 40 aggregates. These multivariate effects in bulk solution provide insights into the correlation of pH-, ionic strength- or Zn 2+ ions changes with amyloid deposits in AD brain and will deepen our understanding of the molecular pathology in the local brain microenvironment. 

Abstract The coacervation of alpha‐synuclein (αSyn) into cytotoxic oligomers and amyloid fibrils are considered pathological hallmarks of Parkinson's disease. While aggregation is central to amyloid diseases, liquid–liquid phase separation (LLPS) and its interplay with aggregation have gained increasing interest. Previous work shows that factors promoting or inhibiting aggregation have similar effects on LLPS. This study provides a detailed scanning of a wide range of parameters, including protein, salt and crowding concentrations at multiple pH values, revealing different salt dependencies of aggregation and LLPS. The influence of salt on aggregation under crowding conditions follows a non‐monotonic pattern, showing increased effects at medium salt concentrations. This behavior can be elucidated through a combination of electrostatic screening and salting‐out effects on the intramolecular interactions between the N‐terminal and C‐terminal regions of αSyn. By contrast, this study finds a monotonic salt dependence of LLPS due to intermolecular interactions. Furthermore, it observes time evolution of the two distinct assembly states, with macroscopic fibrillar‐like bundles initially forming at medium salt concentration but subsequently converting into droplets after prolonged incubation. The droplet state is therefore capable of inhibiting aggregation or even dissolving aggregates through heterotypic interactions, thus preventing αSyn from its dynamically arrested state.