Diversity of N-terminal Sequences of Aβ Peptides Governs TDMQ20-Mediated CuII Extraction Efficiency and Kinetics

Alzheimer’s disease (AD) is recognized as the most common form of dementia, with no curative therapies available. One of the current strategies towards an AD drug focuses on the development of copper-binding ligands capable of extracting CuII ions from β-amyloid (Aβ) peptides, among which TDMQ20 has attracted considerable attention. However, previous studies of TDMQ20 have focused primarily on its interaction with Aβ(1–x) peptides, with no consideration given to the molecular heterogeneity of Aβ species present in the AD brain. In this work, we investigated the impact of two biologically relevant N-terminal truncations (4-x) and (5-x) on the formation of the CuIITDMQ20 complex, guided by their known avidity to bind CuII ions. These sequences were represented by water-soluble-(non-aggregating) Aβ(4–16) and Aβ(5–16) peptides. We also reevaluated the CuII-binding properties of TDMQ20 and its interaction with the standard CuIIAβ(1–16) complex. Using stopped-flow kinetics, we confirmed the immediate and complete extraction of CuII ion from CuIIAβ(1–16) complex in the presence of equimolar TDMQ20. Importantly, however, CuIIAβ(4–16) and CuIIAβ(5–16) exhibited marked resistance to TDMQ20-mediated demetallation, revealing strong dependence of CuII extraction on the Aβ sequence. These findings suggest that the heterogeneity of Aβ species in AD-affected brains can be an important factor determining the efficacy of CuII-targeting therapeutic strategies.