Glycosaminoglycans Promote Amyloid-β Aggregation via Multivalent, pH-Dependent Interactions

Glycosaminoglycans (GAGs) are polyanionic polysaccharides that co-localize with amyloid-β (Aβ) deposits in Alzheimer’s disease, yet their mechanistic contribution to Aβ aggregation remains unclear. Here, we show that GAGs function as pH-responsive electrostatic scaffolds that selectively accelerate Aβ(1–42) aggregation under mildly acidic, endosomal conditions but not at neutral extracellular pH. Combining experimental and computational approaches, we identify protonated N-terminal histidines as key determinants of GAG binding. Weak interactions between GAGs and the charged Nterminal region of Aβ promote conformational rearrangements that bring peptides into proximity and expose adjacent hydrophobic aggregation-prone segments, thereby facilitating peptide clustering. Kinetic analyses reveal that aggregation is enhanced in a way consistent with an apparent increase in effective peptide concentration, accelerating nucleation without altering the dominant aggregation pathway. Systematic variation of GAG chain length and sulfation level further demonstrates that aggregation enhancement requires a threshold degree of multivalency, consistent with a clustering-driven mechanism. Together, these findings establish a framework in which pH-dependent electrostatic interactions with GAGs act as molecular triggers of amyloid nucleation, providing insight into how cellular microenvironments regulate the earliest stages of Alzheimer’s disease pathology.