title: Amyloid-beta oligomerization is associated with the generation of a typical peptide fragment fingerprint.
abstract: Amyloid-beta (Aβ) peptide oligomerization plays a central role in the pathogenesis of Alzheimer's disease (AD), and Aβ oligomers are collectively considered an appealing therapeutic target for the treatment of AD. However, the molecular mechanisms leading to the pathologic accumulation of oligomers are unclear, and the exact structural composition of oligomers is being debated. Using targeted and quantitative mass spectrometry, we reveal site-specific Aβ autocleavage during the early phase of aggregation, producing a typical Aβ fragment signature and that truncated Aβ peptides can form stable oligomeric complexes with full-length Aβ peptide. We show that the use of novel anti-Aβ antibodies raised against these truncated Aβ isoforms allows for monitoring and targeting the accumulation of truncated Aβ fragments. Antibody-enabled screening of transgenic models of AD as well as human postmortem brain tissue and cerebrospinal fluid revealed that aggregation-associated Aβ cleavage is a highly relevant clinical feature of AD.
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Nikita
authors.initials: N
authors.lastname: Rudinskiy
authors.affiliation: School of Life Sciences, Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Fuerer
authors.affiliation: School of Basic Sciences, Interdisciplinary Centre for Electron Microscopy (CIME), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Demurtas
authors.affiliation: School of Life Sciences, Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zamorano
authors.affiliation: School of Life Sciences, Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Cyntia
authors.initials: C
authors.lastname: De Piano
authors.affiliation: Center for Cognitive and Neural Systems, The University of Edinburgh, Edinburgh, Scotland; Centre for Dementia Prevention, The University of Edinburgh, Edinburgh, Scotland; Euan MacDonald Centre for Motorneurone Disease, The University of Edinburgh, Edinburgh, Scotland.
authors.forename: Abigail G
authors.initials: AG
authors.lastname: Herrmann
authors.affiliation: Center for Cognitive and Neural Systems, The University of Edinburgh, Edinburgh, Scotland; Centre for Dementia Prevention, The University of Edinburgh, Edinburgh, Scotland; Euan MacDonald Centre for Motorneurone Disease, The University of Edinburgh, Edinburgh, Scotland.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spires-Jones
authors.affiliation: Department of Neurology, Ulm University Hospital, Ulm, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Oeckl
authors.affiliation: Department of Neurology, Ulm University Hospital, Ulm, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Otto
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Massachusetts General Institute for Neurodegenerative Disease, Charlestown, MA, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: School of Life Sciences, Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Moniatte
authors.affiliation: Department of Neurology, Alzheimer's Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: School of Life Sciences, Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. Electronic address: adrien.schmid@epfl.ch.
authors.forename: Adrien W
authors.initials: AW
authors.lastname: Schmid
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001323:Autoantibodies; D001921:Brain / Q000378:metabolism; D002850:Chromatography, Gel; D002853:Chromatography, Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D015151:Immunoblotting; D013058:Mass Spectrometry; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D001323:Autoantibodies; D010446:Peptide Fragments; D020033:Protein Isoforms; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Aggregation; Alzheimer's disease; Autocleavage; C-terminal amidation; Mass spectrometry; Oligomers; Selected reaction monitoring