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Phage display and k...
Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication
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- Munke, Anna (author)
- Uppsala universitet,Molekylär biofysik,Lund Univ, Chem Ctr, Dept Biochem & Struct Biol, SE-22100 Lund, Sweden,Lund University
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- Persson, Jonas (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Lund Univ, Chem Ctr, Dept Biochem & Struct Biol, SE-22100 Lund, Sweden,Lund University,University of Cambridge
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- Weiffert, Tanja (author)
- Lund University,Lunds universitet,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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- De Genst, Erwin (author)
- Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England.; Astra Zeneca, Innovat Med, Discovery Sci, Cambridge CB4 0WG, England,University of Cambridge
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- Meisl, Georg (author)
- Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England,University of Cambridge
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- Arosio, Paolo (author)
- Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England.; ETH, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland,University of Cambridge
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- Carnerup, Anna (author)
- Lund University,Lunds universitet,Fysikalisk kemi,Enheten för fysikalisk och teoretisk kemi,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Physical Chemistry,Physical and theoretical chemistry,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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- Dobson, Christopher M. (author)
- Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England,University of Cambridge
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- Vendruscolo, Michele (author)
- Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England,University of Cambridge
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- Knowles, Tuomas P. J. (author)
- Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England.; Univ Cambridge, Dept Phys, Cavendish Lab, Cambridge CB3 0HE, England
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- Linse, Sara (author)
- Lund University,Lunds universitet,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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(creator_code:org_t)
- 2017-06-05
- 2017
- 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. ; 114:25, s. 6444-6449
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https://doi.org/10.1...
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https://www.pnas.org...
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http://dx.doi.org/10...
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https://urn.kb.se/re...
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Abstract
Subject headings
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- The aggregation of the amyloid β peptide (Aβ) into amyloid fibrils is a defining characteristic of Alzheimer’s disease. Because of the complexity of this aggregation process, effective therapeutic inhibitors will need to target the specific microscopic steps that lead to the production of neurotoxic species. We introduce a strategy for generating fibril-specific antibodies that selectively suppress fibril-dependent secondary nucleation of the 42-residue form of Aβ (Aβ42). We target this step because it has been shown to produce the majority of neurotoxic species during aggregation of Aβ42. Starting from large phage display libraries of single-chain antibody fragments (scFvs), the three-stage approach that we describe includes (i) selection of scFvs with high affinity for Aβ42 fibrils after removal of scFvs that bind Aβ42 in its monomeric form; (ii) ranking, by surface plasmon resonance affinity measurements, of the resulting candidate scFvs that bind to the Aβ42 fibrils; and (iii) kinetic screening and analysis to find the scFvs that inhibit selectively the fibril-catalyzed secondary nucleation process in Aβ42 aggregation. By applying this approach, we have identified four scFvs that inhibit specifically the fibril-dependent secondary nucleation process. Our method also makes it possible to discard antibodies that inhibit elongation, an important factor because the suppression of elongation does not target directly the production of toxic oligomers and may even lead to its increase. On the basis of our results, we suggest that the method described here could form the basis for rationally designed immunotherapy strategies to combat Alzheimer’s and related neurodegenerative diseases.
Subject headings
- NATURVETENSKAP -- Kemi -- Fysikalisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Physical Chemistry (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- Alzheimer
- antibody
- inhibitor
- drug development
- self-assembly
- Alzheimer
- Antibody
- Drug development
- Inhibitor
- Self-assembly
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Munke, Anna
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Persson, Jonas
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Weiffert, Tanja
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De Genst, Erwin
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Meisl, Georg
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Arosio, Paolo
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show more...
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Carnerup, Anna
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Dobson, Christop ...
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Vendruscolo, Mic ...
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Knowles, Tuomas ...
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Linse, Sara
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Physical Chemist ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biophysics
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
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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 ...
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Proceedings of t ...
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Uppsala University
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Lund University