1. Anti-ADDL antibodies differentially block oligomer binding to hippocampal neurons.
- Author
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Shughrue PJ, Acton PJ, Breese RS, Zhao WQ, Chen-Dodson E, Hepler RW, Wolfe AL, Matthews M, Heidecker GJ, Joyce JG, Villarreal SA, and Kinney GG
- Subjects
- Alzheimer Disease metabolism, Animals, Cell Line, Tumor, Cells, Cultured, Cerebral Cortex metabolism, Dendritic Spines physiology, Hippocampus cytology, Humans, In Vitro Techniques, Ligands, Mice, Mice, Inbred BALB C, Neuropeptides metabolism, Protein Binding, Rats, Rats, Sprague-Dawley, Synapses physiology, Amyloid beta-Peptides immunology, Amyloid beta-Peptides metabolism, Antibodies immunology, Hippocampus metabolism, Neurons metabolism, Peptide Fragments immunology, Peptide Fragments metabolism
- Abstract
Abeta-derived diffusible ligands (ADDLs) are abundant in AD brain, bind to hippocampal neurons and induce deficits in rodent cognition. To further investigate ADDL binding to neurons and identify antibodies that block this association, a panel of anti-Abeta and anti-ADDL antibodies was characterized for their ability to immuno-detect neuronally bound ADDLs and attenuate the binding of ADDLs to neurons. The results showed that anti-Abeta and anti-ADDL antibodies were able to abate ADDLs binding to hippocampal neurons, but to different degrees. Quantitative assessment of binding showed that one antibody, ACU-954 was markedly more effective at blocking ADDL binding than other antibodies assessed. ACU-954 was also found to block ADDL binding to hippocampal slice cultures, attenuate the ADDL-induced loss of dendritic spines and detect "natural ADDLs" in human AD tissue. These results demonstrated that antibodies that bind to and block ADDL binding to neurons can be identified, although their efficacy is conformationally specific since it is not readily apparent or predictable based on the core linear epitope or affinity for monomeric Abeta.
- Published
- 2010
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