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

作者：Taddei K; Laws S M; Verdile G; Munns S; D'Costa K; Harvey A R; Martins I J; Hill F; Levy E; Shaw J E; Martins R N^*

来源：Neurobiology of Aging, 2010, 31(2): 203-214.

DOI：10.1016/j.neurobiolaging.2008.03.023

• Phage display
• Peptides
• Beta amyloid
• Neutralization
• Drug development

Amyloid-beta (A beta) 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 A beta (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 A beta'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 A beta (40 or 42). Here, we show that two of the three most enriched peptides obtained significantly reduced A beta 42's SOD-like activity. A 15-mer peptide reduced A beta 42 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 A beta'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 A beta-induced neurotoxicity and thus provide promising leads for rational drug development.

• 出版日期2010-2