A Copper-Binding Peptide with Therapeutic Potential against Alzheimer′s Disease: From the Blood–Brain Barrier to Metal Competition

Alzheimer's disease (AD) is the most common form of dementia worldwide. AD brains are characterized by the accumulation of amyloid-β peptides (Aβ) that bind Cu²⁺ and have been associated with several neurotoxic mechanisms. Although the use of copper chelators to prevent the formation of Cu²⁺-Aβ complexes has been proposed as a therapeutic strategy, recent studies show that copper is an important neuromodulator that is essential for a neuroprotective mechanism mediated by Cu²⁺ binding to the cellular prion protein (PrP^C). Therefore, in addition to metal selectivity and blood-brain barrier (BBB) permeability, an emerging challenge for copper chelators is to prevent the formation of neurotoxic Cu²⁺-Aβ species without perturbing the neuroprotective Cu²⁺-PrP^C interaction. Previously, we reported the design of a tetrapeptide (TP) that withdraws Cu²⁺ from Aβ(1-16) and impacts the Cu²⁺-induced aggregation of Aβ(1-40). In this study, we improved the drug-like properties of TP in a BBB model, evaluated the metal selectivity of the optimized peptide (TP*), and tested its effect on Cu²⁺ coordination to PrP^C and proteins involved in copper trafficking, such as copper transporter 1 and albumin. Our results show that changing the stereochemistry of the first residue prevents TP degradation in the BBB model and coadministration of TP with a peptide that increases BBB permeability allows its passage through the BBB model. TP* is highly selective toward Cu²⁺ in the presence of Zn²⁺ ions, transfers Cu²⁺ to copper-trafficking proteins, and forms a ternary TP*-Cu²⁺-PrP species that does not perturb the physiological conformation of PrP and displays only a minor impact in the neuroprotective Cu²⁺-dependent interaction of PrP^C with the <i>N</i>-methyl-d-aspartate receptor. Overall, these results show that TP* displays desirable features for a copper chelator with therapeutic potential against AD. Moreover, this is the first study that explores the effect of a Cu²⁺ chelator with therapeutic potential for AD on Cu²⁺ coordination to PrP^C (an emerging key player in AD pathology), integrating recent knowledge about metalloproteins involved in AD with the design of copper chelators against AD.