Selective targeting of primary and secondary nucleation pathways in A?42 aggregation using a rational antibody scanning method.

ABSTRACT: Antibodies targeting A?42 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 A?42. Each antibody in the panel is rationally designed to target a specific linear epitope, with the selected epitopes scanning the A?42 sequence. By screening in vitro the panel to identify the specific microscopic steps in the A?42 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 A?42 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 A?42. 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.

SUBMITTER: Aprile FA 

PROVIDER: S-EPMC5479649 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature