Small angle X-ray scattering analysis of Cu 2+ -induced oligomers of the Alzheimer's amyloid β peptide
Research into causes of Alzheimer's disease and its treatment has produced a tantalising array of hypotheses about the role of transition metal dyshomeostasis, many of them on the interaction of these metals with the neurotoxic amyloid-β peptide (Aβ). Here, we have used small angle X-ray scatte...
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| Veröffentlicht in: | Metallomics 2015, Vol.7 (3), p.536-543 |
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| creator | Ryan, Timothy M. Kirby, Nigel Mertens, Haydyn D. T. Roberts, Blaine Barnham, Kevin J. Cappai, Roberto Pham, Chi Le Lan Masters, Colin L. Curtain, Cyril C. |
| description | Research into causes of Alzheimer's disease and its treatment has produced a tantalising array of hypotheses about the role of transition metal dyshomeostasis, many of them on the interaction of these metals with the neurotoxic amyloid-β peptide (Aβ). Here, we have used small angle X-ray scattering (SAXS) to study the effect of the molar ratio, Cu
2+
/Aβ, on the early three-dimensional structures of the Aβ
1–40
and Cu
2+
/Aβ
1–42
peptides in solution. We found that at molar ratios of 0.5 copper to peptide Aβ
1–40
aggregated, while Aβ
1–42
adopted a relatively monodisperse cylindrical shape, and at a ratio of 1.5 copper to peptide Aβ
1–40
adopted a monodisperse cylindrical shape, while Aβ
1–42
adopted the shape of an ellipsoid of rotation. We also found,
via
in-line rapid mixing SAXS analysis, that both peptides in the absence of copper were monodisperse at very short timeframes ( |
| doi_str_mv | 10.1039/C4MT00323C |
| format | Article |
| fullrecord | <record><control><sourceid>crossref</sourceid><recordid>TN_cdi_crossref_primary_10_1039_C4MT00323C</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>10_1039_C4MT00323C</sourcerecordid><originalsourceid>FETCH-LOGICAL-c76C-18e8aea72ea7d0a2d06d3cf563165cf6714c246b9e67ab8a19f9bab96ef7f6d43</originalsourceid><addsrcrecordid>eNpFkM1KxDAcxIMouK5efILcBKWaNG3aHpfiF6x4sIe9lX-Tf7qRdFuS7qE-lg_iM1k_0MMww29gDkPIOWfXnInipkyeKsZELMoDsuBZKqO04JvDv8z4MTkJ4ZUxmTCWLkj70oFzFHatQ7qJPEw0KBhH9HbXzhjcFGygvaHlnsZXNLI7vVeoae9s23fov7txi3Tl3rZoZ3IRKHST662mH-90wGG0Gk_JkQEX8OzXl6S6u63Kh2j9fP9YrtaRymQZ8RxzQMjiWZpBrJnUQplUCi5TZWTGExUnsilQZtDkwAtTNNAUEk1mpE7Eklz-zCrfh-DR1IO3Hfip5qz-eqj-f0h8AhUIWj0</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Small angle X-ray scattering analysis of Cu 2+ -induced oligomers of the Alzheimer's amyloid β peptide</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>Royal Society Of Chemistry Journals 2008-</source><creator>Ryan, Timothy M. ; Kirby, Nigel ; Mertens, Haydyn D. T. ; Roberts, Blaine ; Barnham, Kevin J. ; Cappai, Roberto ; Pham, Chi Le Lan ; Masters, Colin L. ; Curtain, Cyril C.</creator><creatorcontrib>Ryan, Timothy M. ; Kirby, Nigel ; Mertens, Haydyn D. T. ; Roberts, Blaine ; Barnham, Kevin J. ; Cappai, Roberto ; Pham, Chi Le Lan ; Masters, Colin L. ; Curtain, Cyril C.</creatorcontrib><description>Research into causes of Alzheimer's disease and its treatment has produced a tantalising array of hypotheses about the role of transition metal dyshomeostasis, many of them on the interaction of these metals with the neurotoxic amyloid-β peptide (Aβ). Here, we have used small angle X-ray scattering (SAXS) to study the effect of the molar ratio, Cu
2+
/Aβ, on the early three-dimensional structures of the Aβ
1–40
and Cu
2+
/Aβ
1–42
peptides in solution. We found that at molar ratios of 0.5 copper to peptide Aβ
1–40
aggregated, while Aβ
1–42
adopted a relatively monodisperse cylindrical shape, and at a ratio of 1.5 copper to peptide Aβ
1–40
adopted a monodisperse cylindrical shape, while Aβ
1–42
adopted the shape of an ellipsoid of rotation. We also found,
via
in-line rapid mixing SAXS analysis, that both peptides in the absence of copper were monodisperse at very short timeframes (<2 s). Kratky plots of these scattering profiles indicated that immediately after mixing both were intrinsically disordered. Ensemble optimisation modelling reflected this, indicating a wide range of structural conformers. These data reflect the ensembles from which the Cu
2+
-promoted oligomers were derived. Our results are discussed in the light of other studies that have shown that the Cu
2+
/Aβ has a marked effect on fibril and oligomer formation by this peptide, with a higher ratio favouring the formation of cytotoxic non-amyloid oligomers. Our results are relatively consistent with previous two-dimensional studies of the conformations of these Cu
2+
-induced entities, made on a much longer time-scale than SAXS, by transmission electron microscopy and atomic force microscopy, which showed that a range of oligomeric species are formed. We propose that SAXS carried out on a modern synchrotron beamline enables studies on initial events in disordered protein folding on physiologically-relevant time-scales, and will likely provide great insight into the initiating processes of the Aβ misfolding, oligomerisation and amyloid formation.</description><identifier>ISSN: 1756-5901</identifier><identifier>EISSN: 1756-591X</identifier><identifier>DOI: 10.1039/C4MT00323C</identifier><language>eng</language><ispartof>Metallomics, 2015, Vol.7 (3), p.536-543</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c76C-18e8aea72ea7d0a2d06d3cf563165cf6714c246b9e67ab8a19f9bab96ef7f6d43</citedby><cites>FETCH-LOGICAL-c76C-18e8aea72ea7d0a2d06d3cf563165cf6714c246b9e67ab8a19f9bab96ef7f6d43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,4024,27923,27924,27925</link.rule.ids></links><search><creatorcontrib>Ryan, Timothy M.</creatorcontrib><creatorcontrib>Kirby, Nigel</creatorcontrib><creatorcontrib>Mertens, Haydyn D. T.</creatorcontrib><creatorcontrib>Roberts, Blaine</creatorcontrib><creatorcontrib>Barnham, Kevin J.</creatorcontrib><creatorcontrib>Cappai, Roberto</creatorcontrib><creatorcontrib>Pham, Chi Le Lan</creatorcontrib><creatorcontrib>Masters, Colin L.</creatorcontrib><creatorcontrib>Curtain, Cyril C.</creatorcontrib><title>Small angle X-ray scattering analysis of Cu 2+ -induced oligomers of the Alzheimer's amyloid β peptide</title><title>Metallomics</title><description>Research into causes of Alzheimer's disease and its treatment has produced a tantalising array of hypotheses about the role of transition metal dyshomeostasis, many of them on the interaction of these metals with the neurotoxic amyloid-β peptide (Aβ). Here, we have used small angle X-ray scattering (SAXS) to study the effect of the molar ratio, Cu
2+
/Aβ, on the early three-dimensional structures of the Aβ
1–40
and Cu
2+
/Aβ
1–42
peptides in solution. We found that at molar ratios of 0.5 copper to peptide Aβ
1–40
aggregated, while Aβ
1–42
adopted a relatively monodisperse cylindrical shape, and at a ratio of 1.5 copper to peptide Aβ
1–40
adopted a monodisperse cylindrical shape, while Aβ
1–42
adopted the shape of an ellipsoid of rotation. We also found,
via
in-line rapid mixing SAXS analysis, that both peptides in the absence of copper were monodisperse at very short timeframes (<2 s). Kratky plots of these scattering profiles indicated that immediately after mixing both were intrinsically disordered. Ensemble optimisation modelling reflected this, indicating a wide range of structural conformers. These data reflect the ensembles from which the Cu
2+
-promoted oligomers were derived. Our results are discussed in the light of other studies that have shown that the Cu
2+
/Aβ has a marked effect on fibril and oligomer formation by this peptide, with a higher ratio favouring the formation of cytotoxic non-amyloid oligomers. Our results are relatively consistent with previous two-dimensional studies of the conformations of these Cu
2+
-induced entities, made on a much longer time-scale than SAXS, by transmission electron microscopy and atomic force microscopy, which showed that a range of oligomeric species are formed. We propose that SAXS carried out on a modern synchrotron beamline enables studies on initial events in disordered protein folding on physiologically-relevant time-scales, and will likely provide great insight into the initiating processes of the Aβ misfolding, oligomerisation and amyloid formation.</description><issn>1756-5901</issn><issn>1756-591X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNpFkM1KxDAcxIMouK5efILcBKWaNG3aHpfiF6x4sIe9lX-Tf7qRdFuS7qE-lg_iM1k_0MMww29gDkPIOWfXnInipkyeKsZELMoDsuBZKqO04JvDv8z4MTkJ4ZUxmTCWLkj70oFzFHatQ7qJPEw0KBhH9HbXzhjcFGygvaHlnsZXNLI7vVeoae9s23fov7txi3Tl3rZoZ3IRKHST662mH-90wGG0Gk_JkQEX8OzXl6S6u63Kh2j9fP9YrtaRymQZ8RxzQMjiWZpBrJnUQplUCi5TZWTGExUnsilQZtDkwAtTNNAUEk1mpE7Eklz-zCrfh-DR1IO3Hfip5qz-eqj-f0h8AhUIWj0</recordid><startdate>2015</startdate><enddate>2015</enddate><creator>Ryan, Timothy M.</creator><creator>Kirby, Nigel</creator><creator>Mertens, Haydyn D. T.</creator><creator>Roberts, Blaine</creator><creator>Barnham, Kevin J.</creator><creator>Cappai, Roberto</creator><creator>Pham, Chi Le Lan</creator><creator>Masters, Colin L.</creator><creator>Curtain, Cyril C.</creator><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>2015</creationdate><title>Small angle X-ray scattering analysis of Cu 2+ -induced oligomers of the Alzheimer's amyloid β peptide</title><author>Ryan, Timothy M. ; Kirby, Nigel ; Mertens, Haydyn D. T. ; Roberts, Blaine ; Barnham, Kevin J. ; Cappai, Roberto ; Pham, Chi Le Lan ; Masters, Colin L. ; Curtain, Cyril C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c76C-18e8aea72ea7d0a2d06d3cf563165cf6714c246b9e67ab8a19f9bab96ef7f6d43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ryan, Timothy M.</creatorcontrib><creatorcontrib>Kirby, Nigel</creatorcontrib><creatorcontrib>Mertens, Haydyn D. T.</creatorcontrib><creatorcontrib>Roberts, Blaine</creatorcontrib><creatorcontrib>Barnham, Kevin J.</creatorcontrib><creatorcontrib>Cappai, Roberto</creatorcontrib><creatorcontrib>Pham, Chi Le Lan</creatorcontrib><creatorcontrib>Masters, Colin L.</creatorcontrib><creatorcontrib>Curtain, Cyril C.</creatorcontrib><collection>CrossRef</collection><jtitle>Metallomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ryan, Timothy M.</au><au>Kirby, Nigel</au><au>Mertens, Haydyn D. T.</au><au>Roberts, Blaine</au><au>Barnham, Kevin J.</au><au>Cappai, Roberto</au><au>Pham, Chi Le Lan</au><au>Masters, Colin L.</au><au>Curtain, Cyril C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Small angle X-ray scattering analysis of Cu 2+ -induced oligomers of the Alzheimer's amyloid β peptide</atitle><jtitle>Metallomics</jtitle><date>2015</date><risdate>2015</risdate><volume>7</volume><issue>3</issue><spage>536</spage><epage>543</epage><pages>536-543</pages><issn>1756-5901</issn><eissn>1756-591X</eissn><abstract>Research into causes of Alzheimer's disease and its treatment has produced a tantalising array of hypotheses about the role of transition metal dyshomeostasis, many of them on the interaction of these metals with the neurotoxic amyloid-β peptide (Aβ). Here, we have used small angle X-ray scattering (SAXS) to study the effect of the molar ratio, Cu
2+
/Aβ, on the early three-dimensional structures of the Aβ
1–40
and Cu
2+
/Aβ
1–42
peptides in solution. We found that at molar ratios of 0.5 copper to peptide Aβ
1–40
aggregated, while Aβ
1–42
adopted a relatively monodisperse cylindrical shape, and at a ratio of 1.5 copper to peptide Aβ
1–40
adopted a monodisperse cylindrical shape, while Aβ
1–42
adopted the shape of an ellipsoid of rotation. We also found,
via
in-line rapid mixing SAXS analysis, that both peptides in the absence of copper were monodisperse at very short timeframes (<2 s). Kratky plots of these scattering profiles indicated that immediately after mixing both were intrinsically disordered. Ensemble optimisation modelling reflected this, indicating a wide range of structural conformers. These data reflect the ensembles from which the Cu
2+
-promoted oligomers were derived. Our results are discussed in the light of other studies that have shown that the Cu
2+
/Aβ has a marked effect on fibril and oligomer formation by this peptide, with a higher ratio favouring the formation of cytotoxic non-amyloid oligomers. Our results are relatively consistent with previous two-dimensional studies of the conformations of these Cu
2+
-induced entities, made on a much longer time-scale than SAXS, by transmission electron microscopy and atomic force microscopy, which showed that a range of oligomeric species are formed. We propose that SAXS carried out on a modern synchrotron beamline enables studies on initial events in disordered protein folding on physiologically-relevant time-scales, and will likely provide great insight into the initiating processes of the Aβ misfolding, oligomerisation and amyloid formation.</abstract><doi>10.1039/C4MT00323C</doi><tpages>8</tpages></addata></record> |
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| ispartof | Metallomics, 2015, Vol.7 (3), p.536-543 |
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| source | Oxford University Press Journals All Titles (1996-Current); Royal Society Of Chemistry Journals 2008- |
| title | Small angle X-ray scattering analysis of Cu 2+ -induced oligomers of the Alzheimer's amyloid β peptide |
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