A genetically encoded selection for amyloid-β oligomer binders
Open accessPublished version of a preprint
Abstract
Soluble amyloid-β oligomers (AβOs) are a hypothesized source of neurotoxicity in Alzheimer disease. Binding proteins that recognize these species may have high utility in diagnostic and therapeutic applications. However, identifying binders to AβOs directly generated from the aggregation cascade is challenging because of the short lifetime and low concentrations of oligomer populations. We report a strategy to detect binding to AβOs formed during Aβ42 aggregation using a genetically encoded biosensor. We show that our method enables rapid, highly reproducible measurement of the activity of existing AβO 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 Aβ aggregation thought to generate the highest number of toxic oligomers. Our approach may greatly accelerate the discovery and characterization of binding proteins that target AβOs.
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Cites
Highly accurate protein structure prediction with AlphaFold
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The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
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Vaccination with soluble Aβ oligomers generates toxicity‐neutralizing antibodies
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Role of Aducanumab in the Treatment of Alzheimer’s Disease: Challenges and Opportunities
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Molecular basis of β-amyloid oligomer recognition with a conformational antibody fragment
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- Authors
- Lee, B., Mannone, J. A., & Wang, T.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Wang, Tina
- Venue
- Nature Chemical Biology
- Published
- 2025-07-15
- Volume
- 21
- Issue
- 12
- Pages
- 1885-1894
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W4412420997
- Cited by
- 3
- References
- 6
- Citations by year
- 2026: 3
- FWCI
- 1.68
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Chemical Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (R21AG088715, R01 GM 061238, R35 GM151985)
- National Aeronautics and Space Administration (80NSSC21K0065)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta oligomers, genetically encoded biosensors, binder selection, secondary nucleation, Alzheimer's disease, protein aggregation
- MeSH terms
- Alzheimer Disease, Humans, Peptide Fragments, Protein Binding, Biosensing Techniques, Amyloid beta-Peptides
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