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bioRxiv · 10.1101/2025.03.11.642651

A genetically encoded selection for amyloid-β oligomer binders

Lee, B.·Mannone, J. A.·Wang, T.
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Abstract

Soluble amyloid beta oligomers (A{beta}Os) are a hypothesized source of neurotoxicity in Alzheimers Disease. Binding proteins that recognize these species may have high utility in diagnostic and therapeutic applications. However, identifying binders that recognize A{beta}Os directly generated from the aggregation cascade is made challenging by the short lifetime and low concentrations of oligomer populations. We report a new strategy for detecting binding to A{beta}Os as they form during A{beta}42 aggregation using a genetically encoded biosensor. We show that our method enables rapid and highly reproducible measurement of the activity of existing A{beta}O binders and can be used to select for new binders with improved potency. We uncover hits that are >20 fold more effective than reported binders at delaying secondary nucleation, the step in A{beta} aggregation thought to generate the highest amounts of toxic oligomers. Our approach may greatly accelerate the discovery and characterization of binding proteins that target A{beta}Os.

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Lee, B., Mannone, J. A., Wang, T.. 2025-03-11. A genetically encoded selection for amyloid-β oligomer binders. https://doi.org/10.1101/2025.03.11.642651

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