Accelerated Publications Aβ Protofibrils Possess a Stable Core Structure Resistant to Hydrogen Exchange †
ABSTRACT: Protofibrils are transient structures observed during in vitro formation of mature amyloid fibrils and have been implicated as the toxic species responsible for cell dysfunction and neuronal loss in Alzheimer’s disease (AD) and other protein aggregation diseases. To better understand the r...
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ftciteseerx:oai:CiteSeerX.psu:10.1.1.389.6959 2023-05-15T14:58:43+02:00 Accelerated Publications Aβ Protofibrils Possess a Stable Core Structure Resistant to Hydrogen Exchange † Indu Kheterpal Hilal A. Lashuel Dean M. Hartley Thomas Walz Peter T. Lansbury Ronald Wetzel The Pennsylvania State University CiteSeerX Archives 2003 application/pdf http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.389.6959 http://walz.med.harvard.edu/Publications/PDFs/Kheterpal-Biochem-2003.pdf en eng http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.389.6959 http://walz.med.harvard.edu/Publications/PDFs/Kheterpal-Biochem-2003.pdf Metadata may be used without restrictions as long as the oai identifier remains attached to it. http://walz.med.harvard.edu/Publications/PDFs/Kheterpal-Biochem-2003.pdf text 2003 ftciteseerx 2016-09-18T00:42:40Z ABSTRACT: Protofibrils are transient structures observed during in vitro formation of mature amyloid fibrils and have been implicated as the toxic species responsible for cell dysfunction and neuronal loss in Alzheimer’s disease (AD) and other protein aggregation diseases. To better understand the roles of protofibrils in amyloid assembly and Alzheimer’s disease, we characterized secondary structural features of these heterogeneous and metastable assembly intermediates. We chromatographically isolated different size populations of protofibrils from amyloid assembly reactions of Aβ(1-40), both wild type and the Arctic variant associated with early onset familial AD, and exposed them to hydrogen-deuterium exchange analysis monitored by mass spectrometry (HX-MS). We show that HX-MS can distinguish among unstructured monomer, protofibrils, and fibrils by their different protection patterns. We find that about 40 % of the backbone amide hydrogens of Aβ protofibrils are highly resistant to exchange with deuterium even after 2 days of incubation in aqueous deuterated buffer, implying a very stable, presumably H-bonded, core structure. This is in contrast to mature amyloid fibrils, whose equally stable structure protects about 60 % of the backbone amide hydrogens over the same time frame. We also find a surprising degree of specificity in amyloid assembly, in that wild type Aβ is preferentially excluded from both protofibrils and fibrils grown from an equimolar mixture of wild type and Arctic mutant peptides. These and other Text Arctic Unknown Arctic |
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ABSTRACT: Protofibrils are transient structures observed during in vitro formation of mature amyloid fibrils and have been implicated as the toxic species responsible for cell dysfunction and neuronal loss in Alzheimer’s disease (AD) and other protein aggregation diseases. To better understand the roles of protofibrils in amyloid assembly and Alzheimer’s disease, we characterized secondary structural features of these heterogeneous and metastable assembly intermediates. We chromatographically isolated different size populations of protofibrils from amyloid assembly reactions of Aβ(1-40), both wild type and the Arctic variant associated with early onset familial AD, and exposed them to hydrogen-deuterium exchange analysis monitored by mass spectrometry (HX-MS). We show that HX-MS can distinguish among unstructured monomer, protofibrils, and fibrils by their different protection patterns. We find that about 40 % of the backbone amide hydrogens of Aβ protofibrils are highly resistant to exchange with deuterium even after 2 days of incubation in aqueous deuterated buffer, implying a very stable, presumably H-bonded, core structure. This is in contrast to mature amyloid fibrils, whose equally stable structure protects about 60 % of the backbone amide hydrogens over the same time frame. We also find a surprising degree of specificity in amyloid assembly, in that wild type Aβ is preferentially excluded from both protofibrils and fibrils grown from an equimolar mixture of wild type and Arctic mutant peptides. These and other |
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The Pennsylvania State University CiteSeerX Archives |
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Text |
author |
Indu Kheterpal Hilal A. Lashuel Dean M. Hartley Thomas Walz Peter T. Lansbury Ronald Wetzel |
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Indu Kheterpal Hilal A. Lashuel Dean M. Hartley Thomas Walz Peter T. Lansbury Ronald Wetzel Accelerated Publications Aβ Protofibrils Possess a Stable Core Structure Resistant to Hydrogen Exchange † |
author_facet |
Indu Kheterpal Hilal A. Lashuel Dean M. Hartley Thomas Walz Peter T. Lansbury Ronald Wetzel |
author_sort |
Indu Kheterpal |
title |
Accelerated Publications Aβ Protofibrils Possess a Stable Core Structure Resistant to Hydrogen Exchange † |
title_short |
Accelerated Publications Aβ Protofibrils Possess a Stable Core Structure Resistant to Hydrogen Exchange † |
title_full |
Accelerated Publications Aβ Protofibrils Possess a Stable Core Structure Resistant to Hydrogen Exchange † |
title_fullStr |
Accelerated Publications Aβ Protofibrils Possess a Stable Core Structure Resistant to Hydrogen Exchange † |
title_full_unstemmed |
Accelerated Publications Aβ Protofibrils Possess a Stable Core Structure Resistant to Hydrogen Exchange † |
title_sort |
accelerated publications aβ protofibrils possess a stable core structure resistant to hydrogen exchange † |
publishDate |
2003 |
url |
http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.389.6959 http://walz.med.harvard.edu/Publications/PDFs/Kheterpal-Biochem-2003.pdf |
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http://walz.med.harvard.edu/Publications/PDFs/Kheterpal-Biochem-2003.pdf |
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http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.389.6959 http://walz.med.harvard.edu/Publications/PDFs/Kheterpal-Biochem-2003.pdf |
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Metadata may be used without restrictions as long as the oai identifier remains attached to it. |
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