Modulation of Aβ1-40 and Aβ4-40 co-assembly by Zinc: getting closer to the biological reality

Alzheimer’s disease (AD), one of the most common neurodegenerative diseases worldwide, is characterised by the self-assembly of amyloid-β peptides (Aβ) in senile plaques, which are also rich in metal ions such as Cu and Zn. Here, we investigated the influence of Zn(II) ions on the self- and co-assembly of Aβ1-40 and the N-terminally truncated Aβ4-40 peptides, the two most prevalent Aβ peptides in the brain. The Zn(II) coordination site in the soluble model peptide Aβ4-16 was investigated for the first time through pH-dependent X-ray absorption spectroscopy and nuclear magnetic resonance measurements, suggesting the formation of two species around neutral pH, depending on the (de)protonation of the N-terminal amine. The Zn(II) affinity was assessed via robust competition experiments, showing that Aβ4-16 has a four-fold lower affinity than Aβ1-16. The self-assembly of Aβ1-40 and Aβ4 40, and their co-assembly were monitored in presence of various Zn(II) levels, which reveals an important concentration-dependent modulatory effect of Zn(II) ions. In particular, the interplay between Zn(II), Aβ1-40 and Aβ4-40, compared to either binary Zn-Aβx-40 systems, promotes the formation of ill-defined assemblies regarded as more toxic than fibrils. This study provides new more-biologically relevant insights on the complex interaction between Zn(II) ions and the two major forms of Aβ peptides detected in the senile plaques, underscoring their significance in the pathophysiology of AD.