Validation and characterisation of a novel peptide that binds monomeric and aggregated beta-amyloid and inhibits the formation of neurotoxic oligomers
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 des...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal Article |
| Published: |
2015
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| Online Access: | http://hdl.handle.net/20.500.11937/21753 |
| _version_ | 1848750678387720192 |
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| author | Barr, R. Verdile, Giuseppe Wijaya, L. Morici, M. Taddei, K. Gupta, V. Pedrini, S. Jin, L. Nicollazzo, J. Knock, E. Fraser, P. Martins, R. |
| author_facet | Barr, R. Verdile, Giuseppe Wijaya, L. Morici, M. Taddei, K. Gupta, V. Pedrini, S. Jin, L. Nicollazzo, J. Knock, E. Fraser, P. Martins, R. |
| author_sort | Barr, R. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T07:40:39Z |
| format | Journal Article |
| id | curtin-20.500.11937-21753 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T07:40:39Z |
| publishDate | 2015 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-217532017-09-13T13:54:25Z Validation and characterisation of a novel peptide that binds monomeric and aggregated beta-amyloid and inhibits the formation of neurotoxic oligomers Barr, R. Verdile, Giuseppe Wijaya, L. Morici, M. Taddei, K. Gupta, V. Pedrini, S. Jin, L. Nicollazzo, J. Knock, E. Fraser, P. Martins, R. 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. 2015 Journal Article http://hdl.handle.net/20.500.11937/21753 10.1074/jbc.M115.679993 fulltext |
| spellingShingle | Barr, R. Verdile, Giuseppe Wijaya, L. Morici, M. Taddei, K. Gupta, V. Pedrini, S. Jin, L. Nicollazzo, J. Knock, E. Fraser, P. Martins, R. Validation and characterisation of a novel peptide that binds monomeric and aggregated beta-amyloid and inhibits the formation of neurotoxic oligomers |
| title | Validation and characterisation of a novel peptide that binds monomeric and aggregated beta-amyloid and inhibits the formation of neurotoxic oligomers |
| title_full | Validation and characterisation of a novel peptide that binds monomeric and aggregated beta-amyloid and inhibits the formation of neurotoxic oligomers |
| title_fullStr | Validation and characterisation of a novel peptide that binds monomeric and aggregated beta-amyloid and inhibits the formation of neurotoxic oligomers |
| title_full_unstemmed | Validation and characterisation of a novel peptide that binds monomeric and aggregated beta-amyloid and inhibits the formation of neurotoxic oligomers |
| title_short | Validation and characterisation of a novel peptide that binds monomeric and aggregated beta-amyloid and inhibits the formation of neurotoxic oligomers |
| title_sort | validation and characterisation of a novel peptide that binds monomeric and aggregated beta-amyloid and inhibits the formation of neurotoxic oligomers |
| url | http://hdl.handle.net/20.500.11937/21753 |