Validation and Characterization of a Novel Peptide That Binds Monomeric and Aggregated ß-Amyloid and Inhibits the Formation of Neurotoxic Oligomers.
J Biol Chem
; 291(2): 547-59, 2016 Jan 08.
Article
em En
| MEDLINE
| ID: mdl-26538562
ABSTRACT
Although the formation of ß-amyloid (Aß) deposits in the brain is a hallmark of Alzheimer disease (AD), the soluble oligomers rather than the mature amyloid fibrils most likely contribute to Aß toxicity and neurodegeneration. Thus, the discovery of agents targeting soluble Aß 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-amino acid peptide (15-mer), isolated via phage display screening, targeted Aß and attenuated its neurotoxicity (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., and Martins, R. N. (2010) Neurobiol. Aging 31, 203-214). The aim of the current study was to generate and biochemically characterize analogues of this peptide with improved stability and therapeutic potential. We demonstrated that a stable analogue of the 15-amino acid peptide (15M S.A.) retained the activity and potency of the parent peptide and demonstrated improved proteolytic resistance in vitro (stable to t = 300 min, c.f. t = 30 min for the parent peptide). This candidate reduced the formation of soluble Aß42 oligomers, with the concurrent generation of non-toxic, insoluble aggregates measuring up to 25-30 nm diameter as determined by atomic force microscopy. The 15M S.A. candidate directly interacted with oligomeric Aß42, as shown by coimmunoprecipitation and surface plasmon resonance/Biacore analysis, with an affinity in the low micromolar range. Furthermore, this peptide bound fibrillar Aß42 and also stained plaques ex vivo in brain tissue from AD model mice. Given its multifaceted ability to target monomeric and aggregated Aß42 species, this candidate holds promise for novel preclinical AD imaging and therapeutic strategies.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Multimerização Proteica
/
Agregados Proteicos
/
Amiloide
/
Neurotoxinas
Tipo de estudo:
Prognostic_studies
/
Screening_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2016
Tipo de documento:
Article