Mapping Hofmeister cation and anion effects on seeded and unseeded aggregation of TDP-43 and amyloid-β in micelle-assisted seed amplification.

Seed-amplification assays (SAA) amplify trace protein aggregates and are being developed for early diagnosis of neurodegenerative diseases. We previously demonstrated that the addition of Brij-58 micelles markedly increases the sensitivity of TDP-43 and Aβ SAA by 100-1000-fold, and established micelle-assisted SAA (mSAA). Here we map Hofmeister cation and anion effects on the aggregation of TDP-43(267-414) and Aβ(M1-42) in mSAA using 15 salts. For TDP-43, kosmotropic anions promoted aggregation whereas chaotropic anions inhibited it; cation trends were weaker and substrate-dependent. By contrast, all salts accelerated Aβ aggregation, with Mg2+ and Ca2+ producing the largest effects. In most cases, seeded and unseeded kinetics shifted in parallel; notably, low guanidinium chloride (110-220 mM) preferentially suppressed seed-independent TDP-43 aggregation, thereby improving seed discrimination. These ion-specific behaviors can be interpreted within a protein-decorated micelle working model in which Aβ aggregation is governed primarily by electrostatic screening, whereas TDP-43 aggregation reflects specific-ion-mediated dehydration of micelles and protein surfaces.