Validation and characterization of a novel peptide that binds monomeric and aggregated β-Amyloid and inhibits the formation of neurotoxic oligomers

Document Type

Journal Article

Publisher

American Society for Biochemistry and Molecular Biology, Inc.

Place of Publication

Bethesda, USA

Faculty

Faculty of Health, Engineering and Science

School

School of Medical and Health Sciences

RAS ID

20344

Funders

National Health and Medical Research Council

Grant Number

NHMRC Number : 595300

Comments

Barr, R. K., Verdile, G., Wijaya, L. K., Morici, M., Taddei, K., Gupta, V. B., ... Martins, R. N. (2016). Validation and characterization of a novel peptide that binds monomeric and aggregated β-Amyloid and inhibits the formation of neurotoxic oligomers. Journal of Biological Chemistry, 291(2), 547-559. Available here

Abstract

Although the formation of beta - amyloid (A β ) deposits in the brain is a hallmark of Alzheimer ’ s Disease (AD), the soluble oligomers rather than the mature amyloid fibrils most likely contribute to A β toxicity and neurodegeneration. Thus, the discovery of agents targeting soluble A β oligomers is highly desirable for early diagnosis prior to the manifestation of a clinical AD phenotype and also more effective therapies. We have previously reported that a novel 15 a.a peptide (15mer), isolated via phage display screening, targeted A β and attenuated its neurotoxicity (1) . The aim of the current study was to generate and biochemically characterise analogues of this peptide with improved stability and therapeutic potential. We demonstrated that a stable analogue of the 15 a.a. peptide (15M S.A.) retained the activity and potency of the parent peptide and demonstrated improved proteolytic resistance in vitro (stable to t=300min c.f. t=30min for the parent peptide). This candidate reduced the formation of soluble A β 42 oligomers, wit h the concurrent generation of non - toxic, insoluble aggregates measuring up to 25 - 30nm diameter as determined by atomic force microscopy. The 15M S.A. candidate directly interacted with oligomeric A β 42, as shown by coimmunoprecipitation and Surface Plasmon Resonance/Biacore analysis, with an affinity in the low micromolar range. Furthermore, this peptide bound fibrillar A β 42 and also stained plaques ex vivo in brain tissue from AD model mice. Given its multifaceted ability to target monomeric and aggregated A β 42 species, this candidate holds promise for novel preclinical AD imaging and therapeutic strategies.

DOI

10.1074/jbc.M115.679993

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free_to_read

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