TY - JOUR
T1 - Generation of nanobodies with conformational specificity for tau oligomers that recognize tau aggregates from human Alzheimer's disease samples
AU - McArthur, Nikki
AU - Squire, Jay D.
AU - Onyeachonam, Ogechukwu J.
AU - Bhatt, Nemil N.
AU - Jerez, Cynthia
AU - Holberton, Abigail L.
AU - Tessier, Peter M.
AU - Wood, Levi B.
AU - Kayed, Rakez
AU - Kane, Ravi S.
N1 - Publisher Copyright:
© 2024 The Royal Society of Chemistry.
PY - 2024/10/22
Y1 - 2024/10/22
N2 - Tauopathies are neurodegenerative diseases that involve tau misfolding and aggregation in the brain. These diseases, including Alzheimer's disease (AD), are some of the least understood and most difficult to treat neurodegenerative disorders. Antibodies and antibody fragments that target tau oligomers, which are especially toxic forms of tau, are promising options for immunotherapies and diagnostic tools for tauopathies. In this study, we have developed conformational, tau oligomer-specific nanobodies, or single-domain antibodies. We demonstrate that these nanobodies, OT2.4 and OT2.6, are highly specific for tau oligomers relative to tau monomers and fibrils. We used epitope mapping to verify that these nanobodies bind to discontinuous epitopes on tau and to support the idea that they interact with a conformation present in the oligomeric, and not monomeric or fibrillar, forms of tau. We show that these nanobodies interact with tau oligomers in brain samples from AD patients and from healthy older adults with primary age-related tauopathy. Our results demonstrate the potential of these nanobodies as tau oligomer-specific binding reagents and future tauopathy therapeutics and diagnostics.
AB - Tauopathies are neurodegenerative diseases that involve tau misfolding and aggregation in the brain. These diseases, including Alzheimer's disease (AD), are some of the least understood and most difficult to treat neurodegenerative disorders. Antibodies and antibody fragments that target tau oligomers, which are especially toxic forms of tau, are promising options for immunotherapies and diagnostic tools for tauopathies. In this study, we have developed conformational, tau oligomer-specific nanobodies, or single-domain antibodies. We demonstrate that these nanobodies, OT2.4 and OT2.6, are highly specific for tau oligomers relative to tau monomers and fibrils. We used epitope mapping to verify that these nanobodies bind to discontinuous epitopes on tau and to support the idea that they interact with a conformation present in the oligomeric, and not monomeric or fibrillar, forms of tau. We show that these nanobodies interact with tau oligomers in brain samples from AD patients and from healthy older adults with primary age-related tauopathy. Our results demonstrate the potential of these nanobodies as tau oligomer-specific binding reagents and future tauopathy therapeutics and diagnostics.
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U2 - 10.1039/d4bm00707g
DO - 10.1039/d4bm00707g
M3 - Article
C2 - 39434503
AN - SCOPUS:85209888675
SN - 2047-4830
VL - 12
SP - 6033
EP - 6046
JO - Biomaterials Science
JF - Biomaterials Science
IS - 23
ER -