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

Aprile, Francesco A.; Sormanni, Pietro; Perni, Michele; Arosio, Paolo; Linse, Sara LU ; Knowles, Tuomas P.J.; Dobson, Christopher M. and Vendruscolo, Michele (2017) In Science Advances 3(6).
Abstract

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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
3
issue
6
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85025668338
ISSN
2375-2548
DOI
10.1126/sciadv.1700488
language
English
LU publication?
yes
id
e6c3c7bc-e945-4ef0-a609-ec29c2b1f038
date added to LUP
2018-09-24 15:01:27
date last changed
2019-10-15 06:45:27
@article{e6c3c7bc-e945-4ef0-a609-ec29c2b1f038,
  abstract     = {<p>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.</p>},
  articleno    = {e1700488},
  author       = {Aprile, Francesco A. and Sormanni, Pietro and Perni, Michele and Arosio, Paolo and Linse, Sara and Knowles, Tuomas P.J. and Dobson, Christopher M. and Vendruscolo, Michele},
  issn         = {2375-2548},
  language     = {eng},
  month        = {06},
  number       = {6},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Advances},
  title        = {Selective targeting of primary and secondary nucleation pathways in Ab42 aggregation using a rational antibody scanning method},
  url          = {http://dx.doi.org/10.1126/sciadv.1700488},
  volume       = {3},
  year         = {2017},
}