Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.05.238105v1?rss=1 Authors: Reyes-Ruiz, J. M., Nakajima, R., Baghallab, I., Goldschmidt, L., Kumosani, T., Felgner, P. L., Glabe, C. G. Abstract: Antibodies against A{beta} amyloid are indispensable research tools and potential therapeutics for Alzheimers Disease, but display unusual properties, such as specificity for aggregated forms of the peptide, ability to distinguish several polymorphic aggregate structures and ability to recognize generic aggregation-related epitopes formed by unrelated amyloid sequences. Understanding the mechanisms underlying these unusual properties of anti-amyloid antibodies and the structures of their corresponding epitopes is crucial for the understanding why they display different therapeutic activities and for the development of more effective therapeutic agents. Here we employed a novel epitomic approach to map the fine structure of the epitopes of 28 monoclonal antibodies against amyloid-beta using immunoselection of random sequences from a phage display, deep sequencing and pattern analysis to define the critical sequence elements recognized by the antibodies. Although most of the antibodies map to linear epitopes in the amino terminal 1-14 residues of A{beta}, the antibodies display differences in the target sequence residues that are critical for binding and in their individual preferences for non-target residues, indicating that the antibodies bind to alternative conformations of the sequence by different mechanisms. Epitomic analysis identifies more non-overlapping sequence A{beta} segments than peptide array approaches that may constitute the conformational epitopes that underly the aggregation specificity of antibodies. Aggregation specific antibodies also recognize sequences that display a significantly higher predicted propensity for forming amyloid than antibodies that recognize A{beta} monomer, indicating that the ability of the random sequences to aggregate into amyloid structures is a critical element of their binding mechanism. Copy rights belong to original authors. Visit the link for more info