Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment.
Oligomers are intermediates of the β-amyloid (Aβ) peptide fibrillogenic pathway and are putative pathogenic culprits in Alzheimer's disease (AD). Here we report the biotechnological generation and biochemical characterization of an oligomer-specific antibody fragment, KW1. KW1 not only discriminates between oligomers and other Aβ conformations, such as fibrils or disaggregated peptide; it also differentiates between different types of Aβ oligomers, such as those formed by Aβ (1-40) and Aβ (1-42) peptide. This high selectivity of binding contrasts sharply with many other conformational antibodies that interact with a large number of structurally analogous but sequentially different antigens. X-ray crystallography, NMR spectroscopy, and peptide array measurements imply that KW1 recognizes oligomers through a hydrophobic and significantly aromatic surface motif that includes Aβ residues 18-20. KW1-positive oligomers occur in human AD brain samples and induce synaptic dysfunctions in living brain tissues. Bivalent KW1 potently neutralizes this effect and interferes with Aβ assembly. By altering a specific step of the fibrillogenic cascade, it prevents the formation of mature Aβ fibrils and induces the accumulation of nonfibrillar aggregates. Our data illuminate significant mechanistic differences in oligomeric and fibril recognition and suggest the considerable potential of KW1 in future studies to detect or inhibit specific types of Aβ conformers.
Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06120 Halle, Saale, Germany.
Isabel
I
Morgado
Karin
K
Wieligmann
Magdalena
M
Bereza
Raik
R
Rönicke
Katrin
K
Meinhardt
Karthikeyan
K
Annamalai
Monika
M
Baumann
Jessica
J
Wacker
Peter
P
Hortschansky
Miroslav
M
Malešević
Christoph
C
Parthier
Christian
C
Mawrin
Cordelia
C
Schiene-Fischer
Klaus G
KG
Reymann
Milton T
MT
Stubbs
Jochen
J
Balbach
Matthias
M
Görlach
Uwe
U
Horn
Marcus
M
Fändrich
D020816:Amino Acid Motifs; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000911:Antibodies, Monoclonal; D018360:Crystallography, X-Ray; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)