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Rational design of a conformation-specific antibody for the quantification of Aβ oligomers

Authors: Francesco A. Aprile, Pietro Sormanni, Marina Podpolny, Shianne Chhangur, Lisa-Maria Needham, Francesco S. Ruggeri, Michele Perni, Ryan Limbocker, Gabriella T. Heller, Tomas Sneideris, Tom Scheidt, Benedetta Mannini, Johnny Habchi, Steven F. Lee, Patricia C. Salinas, Tuomas P. J. Knowles, Christopher M. Dobson, and Michele Vendruscolo

PNAS 2020, 117 (24), 13509-13518. DOI: 10.1073/pnas.1919464117

 

Abstract

Protein misfolding and aggregation is the hallmark of numerous human disorders, including Alzheimer’s disease. This process involves the formation of transient and heterogeneous soluble oligomers, some of which are highly cytotoxic. A major challenge for the development of effective diagnostic and therapeutic tools is thus the detection and quantification of these elusive oligomers.

Here, to address this problem, Aprile et al. develop a two-step rational design method for the discovery of oligomer-specific antibodies. The first step consists of an “antigen scanning” phase in which an initial panel of antibodies is designed to bind different epitopes covering the entire sequence of a target protein. This procedure enables the determination through in vitro assays of the regions exposed in the oligomers but not in the fibrillar deposits.

The second step involves an “epitope mining” phase, in which a second panel of antibodies is designed to specifically target the regions identified during the scanning step. They illustrate this method in the case of the amyloid β (Aβ) peptide, whose oligomers are associated with Alzheimer’s disease. Their results show that this approach enables the accurate detection and quantification of Aβ oligomers in vitro, and in Caenorhabditis elegans and mouse hippocampal tissues.

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InstrumentFluidity One-W Serum
Therapeutic area: antibody affinity, amyloid, neurodegeneration

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