Tau/Aβ chimera peptides: Evaluating the dual function of metal coordination and membrane interaction in one sequence

Abstract

Several abnormal events may concur as major risk factors for Alzheimer's disease (AD) pathogenesis. For instance, dysregulation of brain's metal homeostasis and amyloid-mediated membrane damage are established toxic mechanisms causing neuronal death. In this study, we assess the amyloidogenic propensity and membrane-damage effects, either in the presence or in absence of metal ions, of two newly synthesized bifunctional peptides. These were designed to comprise a metal chelating N-terminus region derived from Tau protein namely the Tau9–16 (EVMEDHAG) or Tau26–33 (QGGYTMHQ) sequences, merged with the C-terminal hydrophobic region analogous to the Amyloid beta (Aβ) 16–20 aminoacid sequence KLVFF (KL). Comparative circular dichroism or fluorescence experiments were carried out to look at the peptide conformation, fibril formation and membrane affinity of Tau9–16KL and Tau26–33KL peptides. We found that Tau9–16KL and Tau26–33KL perturb the fibrillogenic process of Aβ1–40. Furthermore Cu(II) and, to a lower extent, Zn(II) induced conformational changes Tau26–33KL both in water and in membrane-mimicking environment. By contrast, due to a different metal coordination mode we observed for Tau9–16KL an unstructured peptide conformation in all the experimental conditions. Unlike aqueous solution, a certain propensity to form amyloid structures at the lipid membrane interface clearly emerged for both the peptides. However, the two peptides exhibit a different capability to elicit membrane damage depending on the presence or absence of metal ions. Tau9–16KL and Tau26–33KL can be used as peptide-based molecular systems able to interfere with the metal dependent Aβ/Tau cross-seeded generation of membrane active amyloid species.