期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-06377-8
关键词
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资金
- Swedish Research Council (V.R.) [521-2010-2517, 621-2011-581]
- Swedish Brain Foundation [FO2015-0174]
- Wallenberg Center for Protein Research
Protofibrils of the 42 amino acids long amyloid-beta peptide are transient pre-fibrillar intermediates in the process of peptide aggregation into amyloid plaques and are thought to play a critical role in the pathology of Alzheimer's disease. Hence, there is a need for research reagents and potential diagnostic reagents for detection and imaging of such aggregates. Here we describe an in vitro selection of Affibody molecules that bind to protofibrils of A beta(42)cc, which is a stable engineered mimic of wild type A beta(42) protofibrils. Several binders were identified that bind A beta(42)cc protofibrils with low nanomolar affinities, and which also recognize wild type A beta(42) protofibrils. Dimeric head-to-tail fusion proteins with subnanomolar binding affinities, and very slow dissociation off-rates, were also constructed. A mapping of the chemical properties of the side chains onto the Affibody scaffold surface reveals three distinct adjacent surface areas of positively charged surface, nonpolar surface and a polar surface, which presumably match a corresponding surface epitope on the protofibrils. The results demonstrate that the engineered A beta(42)cc is a suitable antigen for directed evolution of affinity reagents with specificity for wild type A beta(42) protofibrils.
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