Selective targeting of primary and secondary nucleation pathways in Ab42 aggregation using a rational antibody scanning method

Antibodies targeting Ab42 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 Ab42. Each antibody in the panel is rationally designed to target a specific linear epitope, with the selected epitopes scanning the Ab42 sequence. By screening in vitro the panel to identify the specific microscopic steps in the Ab42 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 Ab42 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 Ab42. 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.

Sormanni, PietroUniversity of Cambridge (author)
Perni, MicheleUniversity of Cambridge (author)
Arosio, PaoloETH Zürich (author)
Linse, SaraLund University,Lunds universitet,NanoLund: Centre for Nanoscience,Annan verksamhet, LTH,Lunds Tekniska Högskola,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Other operations, LTH,Faculty of Engineering, LTH,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH(Swepub:lu)fkm2-sli (author)
Knowles, Tuomas P.J.University of Cambridge (author)
Dobson, Christopher M.University of Cambridge (author)
Vendruscolo, MicheleUniversity of Cambridge (author)
University of CambridgeETH Zürich (creator_code:org_t)

In:Science Advances: American Association for the Advancement of Science (AAAS)3:62375-2548

By the author/editor: Aprile, Francesc ...; Sormanni, Pietro; Perni, Michele; Arosio, Paolo; Linse, Sara; Knowles, Tuomas ...; show more...; Dobson, Christop ...; Vendruscolo, Mic ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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