title: Validation and Characterization of a Novel Peptide That Binds Monomeric and Aggregated β-Amyloid and Inhibits the Formation of Neurotoxic Oligomers.
abstract: Although the formation of β-amyloid (Aβ) deposits in the brain is a hallmark of Alzheimer disease (AD), the soluble oligomers rather than the mature amyloid fibrils most likely contribute to Aβ toxicity and neurodegeneration. Thus, the discovery of agents targeting soluble Aβ 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 Aβ 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 Aβ42 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 Aβ42, as shown by coimmunoprecipitation and surface plasmon resonance/Biacore analysis, with an affinity in the low micromolar range. Furthermore, this peptide bound fibrillar Aβ42 and also stained plaques ex vivo in brain tissue from AD model mice. Given its multifaceted ability to target monomeric and aggregated Aβ42 species, this candidate holds promise for novel preclinical AD imaging and therapeutic strategies.
authors.affiliation: From the Centre of Excellence for Alzheimer's Disease Research and Care School of Medical Sciences, Edith Cowan University, 270 Joondalup Dr., Joondalup, Western Australia 6027, Alzhyme Pty Ltd., Nedlands, Western Australia 6009.
authors.forename: Renae K
authors.initials: RK
authors.lastname: Barr
authors.affiliation: the School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Western Australia 6102, the Sir James McCusker Alzheimer's Disease Research Unit, Suite 22, Hollywood Medical Centre, 85 Monash Ave., Nedlands, Western Australia 6009, the School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley 6009, giuseppe.verdile@curtin.edu.au.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Verdile
authors.affiliation: From the Centre of Excellence for Alzheimer's Disease Research and Care School of Medical Sciences, Edith Cowan University, 270 Joondalup Dr., Joondalup, Western Australia 6027.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Wijaya
authors.affiliation: From the Centre of Excellence for Alzheimer's Disease Research and Care School of Medical Sciences, Edith Cowan University, 270 Joondalup Dr., Joondalup, Western Australia 6027.
authors.forename: Michael
authors.initials: M
authors.lastname: Morici
authors.affiliation: From the Centre of Excellence for Alzheimer's Disease Research and Care School of Medical Sciences, Edith Cowan University, 270 Joondalup Dr., Joondalup, Western Australia 6027, the Sir James McCusker Alzheimer's Disease Research Unit, Suite 22, Hollywood Medical Centre, 85 Monash Ave., Nedlands, Western Australia 6009.
authors.forename: Kevin
authors.initials: K
authors.lastname: Taddei
authors.affiliation: From the Centre of Excellence for Alzheimer's Disease Research and Care School of Medical Sciences, Edith Cowan University, 270 Joondalup Dr., Joondalup, Western Australia 6027, Alzhyme Pty Ltd., Nedlands, Western Australia 6009, the Sir James McCusker Alzheimer's Disease Research Unit, Suite 22, Hollywood Medical Centre, 85 Monash Ave., Nedlands, Western Australia 6009.
authors.forename: Veer B
authors.initials: VB
authors.lastname: Gupta
authors.affiliation: From the Centre of Excellence for Alzheimer's Disease Research and Care School of Medical Sciences, Edith Cowan University, 270 Joondalup Dr., Joondalup, Western Australia 6027, Alzhyme Pty Ltd., Nedlands, Western Australia 6009, the Sir James McCusker Alzheimer's Disease Research Unit, Suite 22, Hollywood Medical Centre, 85 Monash Ave., Nedlands, Western Australia 6009.
authors.forename: Steve
authors.initials: S
authors.lastname: Pedrini
authors.affiliation: the Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia, and.
authors.forename: Liang
authors.initials: L
authors.lastname: Jin
authors.affiliation: the Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia, and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Nicolazzo
authors.affiliation: the University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, 60 Leonard Ave., Toronto, Ontario M5T 2S8, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Knock
authors.affiliation: the University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, 60 Leonard Ave., Toronto, Ontario M5T 2S8, Canada.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.affiliation: From the Centre of Excellence for Alzheimer's Disease Research and Care School of Medical Sciences, Edith Cowan University, 270 Joondalup Dr., Joondalup, Western Australia 6027, Alzhyme Pty Ltd., Nedlands, Western Australia 6009, the Sir James McCusker Alzheimer's Disease Research Unit, Suite 22, Hollywood Medical Centre, 85 Monash Ave., Nedlands, Western Australia 6009, the School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley 6009, r.martins@ecu.edu.au.
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
mesh_terms: D061605:Administration, Intravenous; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D008822:Mice, Transgenic; D009498:Neurotoxins / Q000633:toxicity*; D010455:Peptides / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects*; D055503:Protein Multimerization / Q000187:drug effects*; D055550:Protein Stability / Q000187:drug effects; D015203:Reproducibility of Results; D012995:Solubility; D020349:Surface Plasmon Resonance; D014316:Tritium / Q000378:metabolism
chemical_list: D000682:Amyloid; D009498:Neurotoxins; D010455:Peptides; D066329:Protein Aggregates; D014316:Tritium
keywords: Alzheimer disease; amyloid-β (AB); imaging; neurodegeneration; peptides