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Stabilization of ne...
Stabilization of neurotoxic Alzheimer amyloid-beta oligomers by protein engineering
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Sandberg, Anders (author)
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Luheshi, Leila M. (author)
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- Söllvander, Sofia (author)
- Uppsala universitet,Geriatrik,Molekylär geriatrik
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Pereira de Barros, Teresa (author)
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Macao, Bertil (author)
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Knowles, Tuomas P. J. (author)
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- Biverstål, Henrik (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för molekylärbiologi,Department of Molecular Biology
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- Lendel, Christofer (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för molekylärbiologi,Department of Molecular Biology
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- Ekholm-Pettersson, Frida (author)
- Uppsala universitet,Geriatrik,Molekylär geriatrik
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- Dubnovitsky, Anatoly (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för molekylärbiologi,Department of Molecular Biology
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- Lannfelt, Lars (author)
- Uppsala universitet,Geriatrik,Molekylär geriatrik
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Dobson, Christopher M. (author)
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- Härd, Torleif (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för molekylärbiologi,Department of Molecular Biology
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(creator_code:org_t)
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- 2010-08-16
- 2010
- English.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:35, s. 15595-15600
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http://www.pnas.org/...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Soluble oligomeric aggregates of the amyloid-beta peptide (Abeta) have been implicated in the pathogenesis of Alzheimer's disease (AD). Although the conformation adopted by Abeta within these aggregates is not known, a beta-hairpin conformation is known to be accessible to monomeric Abeta. Here we show that this beta-hairpin is a building block of toxic Abeta oligomers by engineering a double-cysteine mutant (called Abetacc) in which the beta-hairpin is stabilized by an intramolecular disulfide bond. Abeta(40)cc and Abeta(42)cc both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect Abeta aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in Abetacc oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that beta-sheet-containing Abeta(42)cc oligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type Abeta(42), in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic Abeta oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why Abeta(42) is more toxic than the shorter Abeta(40), and why certain inherited mutations are linked to protofibril formation and early-onset AD.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- amyloid-β peptide
- protein aggregation
- protein structure
- protofibril
- β-hairpin conformation
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Sandberg, Anders
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Luheshi, Leila M ...
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Söllvander, Sofi ...
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Pereira de Barro ...
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Macao, Bertil
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Knowles, Tuomas ...
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show more...
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Biverstål, Henri ...
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Lendel, Christof ...
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Ekholm-Pettersso ...
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Dubnovitsky, Ana ...
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Lannfelt, Lars
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Dobson, Christop ...
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Härd, Torleif
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Proceedings of t ...
- By the university
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Uppsala University
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Swedish University of Agricultural Sciences