Generation of nanobodies with conformational specificity for tau oligomers that recognize tau aggregates from human Alzheimer's disease samples

Nikki McArthur; Jay D Squire; Ogechukwu J Onyeachonam; Nemil N Bhatt; Cynthia Jerez; Abigail L Holberton; Peter M Tessier; Levi B Wood; Rakez Kayed; Ravi S Kane

doi:10.1039/d4bm00707g

Generation of nanobodies with conformational specificity for tau oligomers that recognize tau aggregates from human Alzheimer's disease samples

Biomater Sci. 2024 Oct 22. doi: 10.1039/d4bm00707g. Online ahead of print.

Authors

Nikki McArthur¹, Jay D Squire¹, Ogechukwu J Onyeachonam¹, Nemil N Bhatt^{2

3}, Cynthia Jerez^{2

3}, Abigail L Holberton⁴, Peter M Tessier^{5

6

7

8}, Levi B Wood^{4

9

10}, Rakez Kayed^{2

3}, Ravi S Kane^{1

9

10}

Affiliations

¹ School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA. [email protected].
² Mitchell Center for Neurodegenerative Disease, University of Texas Medical Branch, Galveston, Texas 77555, USA.
³ Department of Neurology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
⁴ George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
⁵ Department of Chemical Engineering, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI 48109, USA.
⁶ Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
⁷ Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
⁹ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
¹⁰ Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.

PMID: 39434503
DOI: 10.1039/d4bm00707g

Abstract

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.