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

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