Antibodies Raised Against an Aβ Oligomer Mimic Recognize Pathological Features in Alzheimer's Disease and Associated Amyloid-Disease Brain Tissue

Abstract

Antibodies that target the {beta}-amyloid peptide (A{beta}) and its associated assemblies are important tools in Alzheimers disease research and have emerged as promising Alzheimers disease therapies. This paper reports the creation and characterization of a triangular A{beta} trimer mimic composed of A{beta}l7-36 {beta}-hairpins, and the generation and study of polyclonal antibodies raised against the A{beta} trimer mimic. The A{beta} trimer mimic is covalently stabilized by three disulfide bonds at the corners of the triangular trimer to create a homogeneous oligomer. Structural, biophysical, and cell-based studies demonstrate that the A{beta} trimer mimic shares characteristics with oligomers of full-length A{beta}: X-ray crystallography elucidates the high-resolution structure of the trimer and reveals that four copies of the trimer assemble to form a dodecamer; SDS-PAGE, size exclusion chromatography, and dynamic light scattering reveal that the trimer also forms higher-order assemblies in solution; cell-based toxicity assays show that the trimer elicits LDH release, decreases ATP levels, and activates caspase-3/7 mediated apoptosis. Tmmunostaining studies on brain slices from people who lived with Alzheimers disease as well as people who lived with Down syndrome reveal that the polyclonal antibodies raised against the A{beta} trimer mimic recognize pathological features including different types of A{beta} plaques and cerebral amyloid angiopathy. These findings suggest that the triangular trimer structural motif is important in Alzheimers disease and may thus constitute a new structurally defined molecular target for diagnostic and therapy development. SYNOPSISA structurally defined A{beta} oligomer mimic is created and studied, and antibodies raised against the A{beta} oligomer mimic are used to investigate its relevance to Alzheimers disease.