Validation and Characterization of a Novel Peptide That Binds Monomeric and Aggregated β-Amyloid and Inhibits the Formation of Neurotoxic Oligomers
Amyloid (mycology)
Characterization
P3 peptide
DOI:
10.1074/jbc.m115.679993
Publication Date:
2015-11-05T01:28:18Z
AUTHORS (12)
ABSTRACT
Although the formation of β-amyloid (Aβ) deposits in brain is a hallmark Alzheimer disease (AD), soluble oligomers rather than mature amyloid fibrils most likely contribute to Aβ toxicity and neurodegeneration. Thus, discovery agents targeting highly desirable for early diagnosis prior manifestation clinical AD phenotype also more effective therapies. We have previously reported that novel 15-amino acid peptide (15-mer), isolated via phage display screening, targeted attenuated its neurotoxicity (Taddei, K., Laws, S. M., Verdile, G., Munns, S., D'Costa, Harvey, A. R., Martins, I. J., Hill, F., Levy, E., Shaw, J. R. N. (2010) Neurobiol. Aging 31, 203-214). The aim current study was generate biochemically characterize analogues this with improved stability therapeutic potential. demonstrated stable analogue (15M S.A.) retained activity potency parent proteolytic resistance vitro (stable t = 300 min, c.f. 30 min peptide). This candidate reduced Aβ42 oligomers, concurrent generation non-toxic, insoluble aggregates measuring up 25-30 nm diameter as determined by atomic force microscopy. 15M S.A. directly interacted oligomeric Aβ42, shown coimmunoprecipitation surface plasmon resonance/Biacore analysis, an affinity low micromolar range. Furthermore, bound fibrillar stained plaques ex vivo tissue from model mice. Given multifaceted ability target monomeric aggregated species, holds promise preclinical imaging strategies.
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