title: Amyloid-β peptide-specific DARPins as a novel class of potential therapeutics for Alzheimer disease.
abstract: Passive immunization with anti-amyloid-β peptide (Aβ) antibodies is effective in animal models of Alzheimer disease. With the advent of efficient in vitro selection technologies, the novel class of designed ankyrin repeat proteins (DARPins) presents an attractive alternative to the immunoglobulin scaffold. DARPins are small and highly stable proteins with a compact modular architecture ideal for high affinity protein-protein interactions. In this report, we describe the selection, binding profile, and epitope analysis of Aβ-specific DARPins. We further showed their ability to delay Aβ aggregation and prevent Aβ-mediated neurotoxicity in vitro. To demonstrate their therapeutic potential in vivo, mono- and trivalent Aβ-specific DARPins (D23 and 3×D23) were infused intracerebroventricularly into the brains of 11-month-old Tg2576 mice over 4 weeks. Both D23 and 3×D23 treatments were shown to result in improved cognitive performance and reduced soluble Aβ levels. These findings demonstrate the therapeutic potential of Aβ-specific DARPins for the treatment of Alzheimer disease.
authors.affiliation: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren.
authors.forename: Michael
authors.initials: M
authors.lastname: Hanenberg
authors.affiliation: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren.
authors.forename: Jordan
authors.initials: J
authors.lastname: McAfoose
authors.affiliation: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren,; Department of Neurology, University Hospital Zurich, University of Zurich, Frauenklinikstrasse 26, 8091 Zurich,; Zurich Center for Integrative Human Physiology and University of Zurich, Winterthurerstrasse 190, 8057 Zurich.
authors.forename: Luka
authors.initials: L
authors.lastname: Kulic
authors.affiliation: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren.
authors.forename: Tobias
authors.initials: T
authors.lastname: Welt
authors.affiliation: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren.
authors.forename: Fabian
authors.initials: F
authors.lastname: Wirth
authors.affiliation: Institute of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, and.
authors.forename: Petra
authors.initials: P
authors.lastname: Parizek
authors.affiliation: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren.
authors.forename: Lisa
authors.initials: L
authors.lastname: Strobel
authors.affiliation: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren.
authors.forename: Susann
authors.initials: S
authors.lastname: Cattepoel
authors.affiliation: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren.
authors.forename: Claudia
authors.initials: C
authors.lastname: Späni
authors.affiliation: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Derungs
authors.affiliation: Neurimmune Holding AG, Wagistrasse 13, 8952 Schlieren, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Maier
authors.affiliation: Institute of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Plückthun
authors.affiliation: Division of Psychiatry Research, University of Zurich, Wagistrasse 12, 8952 Schlieren,. Electronic address: nitsch@bli.uzh.ch.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Nitsch
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017089:Ankyrin Repeat; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins
keywords: Alzheimer Disease; Amyloid; Immunotherapy; Neurodegenerative Disease; Protein Design