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Selective targeting of primary and secondary nucleation pathways in Aβ42 aggregation using a rational antibody scanning method

Published version
Peer-reviewed

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Authors

Aprile, FA 
Arosio, P 
Linse, S 

Abstract

Antibodies targeting Aβ42 are under intense scrutiny because of their therapeutic potential for Alzheimer’s disease. To enable systematic searches, we present an “antibody scanning” strategy for the generation of a panel of antibodies against Aβ42. Each antibody in the panel is rationally designed to target a specific linear epitope, with the selected epitopes scanning the Aβ42 sequence. By screening in vitro the panel to identify the specific microscopic steps in the Aβ42 aggregation process influenced by each antibody, we identify two antibodies that target specifically the primary and the secondary nucleation steps, which are key for the production of Aβ42 oligomers. These two antibodies act, respectively, to delay the onset of aggregation and to block the proliferation of aggregates, and correspondingly reduce the toxicity in a Caenorhabditis elegans model overexpressing Aβ42. These results illustrate how the antibody scanning method described here can be used to readily obtain very small antibody libraries with extensive coverage of the sequences of target proteins.

Description

Keywords

Alzheimer’s disease, protein aggregation, chemical kinetics

Journal Title

Science Advances

Conference Name

Journal ISSN

2375-2548
2375-2548

Volume Title

3

Publisher

American Association for the Advancement of Science
Sponsorship
Alzheimer's Society (317 (AS-SF-16-003))
This work was supported by the Centre for Misfolding Diseases, University of Cambridge. F.A.A. was supported by a Senior Research Fellowship Award from the Alzheimer’s Society, UK (grant number 317, AS-SF-16-003).