Novel phage peptides attenuate beta amyloid-42 catalysed hydrogen peroxide production and associated neurotoxicity

Amyloid-β (Aβ) peptides play a central role in the pathogenesis of Alzheimer's disease. There is accumulating evidence that supports the notion that the toxicity associated with human Aβ (both 40 and 42) is dependent on its superoxide dismutase (SOD)-like activity. We developed a novel screening method involving phage display technology to identify novel peptides capable of inhibiting Aβ's neurotoxicity. Two random peptide libraries containing 6-mer and 15-mer peptide inserts were used and resulted in the identification of 25 peptides that bound human Aβ (40 or 42). Here, we show that two of the three most enriched peptides obtained significantly reduced Aβ42's SOD-like activity. A 15-mer peptide reduced Aβ42 neurotoxicity in a dose-dependent manner as evidenced by a reduction in LDH release. These findings were confirmed in the independent MTT assay. Furthermore, comparative analysis of the 15-mer peptide with Clioquinol, a known inhibitor of Aβ's metal-mediated redox activity, showed the 15-mer peptide to be equipotent to this metal chelator, under the same experimental conditions. These agents represent novel peptides that selectively target and neutralise Aβ-induced neurotoxicity and thus provide promising leads for rational drug development.