2. Academic Validation
  3. Anti-tau antibodies targeting a conformation-dependent epitope selectively bind seeds

Anti-tau antibodies targeting a conformation-dependent epitope selectively bind seeds

  • J Biol Chem. 2023 Nov;299(11):105252. doi: 10.1016/j.jbc.2023.105252.
Brian D Hitt 1,  Ankit Gupta 2,  Ruhar Singh 2,  Ting Yang 2,  Joshua D Beaver 2,  Ping Shang 3,  Charles L White 3rd 3,  Lukasz A Joachimiak 4,  Marc I Diamond 5
Affiliations

Affiliations

  • 1 Center for Alzheimer's and Neurodegenerative Diseases, UT Southwestern Medical Center, Dallas, Texas, USA; Department of Neurology, UT Southwestern Medical Center, Dallas, Texas, USA; Department of Neurology, University of California, Irvine, California, USA.
  • 2 Center for Alzheimer's and Neurodegenerative Diseases, UT Southwestern Medical Center, Dallas, Texas, USA.
  • 3 Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USA; Peter O'Donnell Jr Brain Institute, UT Southwestern Medical Center, Dallas, Texas, USA.
  • 4 Center for Alzheimer's and Neurodegenerative Diseases, UT Southwestern Medical Center, Dallas, Texas, USA; Peter O'Donnell Jr Brain Institute, UT Southwestern Medical Center, Dallas, Texas, USA.
  • 5 Center for Alzheimer's and Neurodegenerative Diseases, UT Southwestern Medical Center, Dallas, Texas, USA; Department of Neurology, UT Southwestern Medical Center, Dallas, Texas, USA; Peter O'Donnell Jr Brain Institute, UT Southwestern Medical Center, Dallas, Texas, USA. Electronic address: marc.diamond@utsouthwestern.edu.
PMID: 37714465 DOI: 10.1016/j.jbc.2023.105252
Abstract

Neurodegenerative tauopathies are caused by the transition of Tau Protein from a monomer to a toxic aggregate. They include Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease (PiD). We have previously proposed that tau monomer exists in two conformational ensembles: an inert form (Mi), which does not self-assemble, and seed-competent form (Ms), which self-assembles and templates ordered assembly growth. We proposed that cis/trans isomerization of tau at P301, the site of dominant disease-associated S/L missense mutations, might underlie the transition of wild-type tau to a seed-competent state. Consequently, we created monoclonal antibodies using non-natural antigens consisting of fluorinated proline (P∗) at the analogous P270 in repeat 1 (R1), biased toward the trans-configuration at either the R1/R2 (TENLKHQP∗GGGKVQIINKK) or the R1/R3 (TENLKHQP∗GGGKVQIVYK) interfaces. Two antibodies, MD2.2 and MD3.1, efficiently immunoprecipitated soluble seeds from AD and PSP but not CBD or PiD brain samples. The antibodies efficiently stained brain samples of AD, PSP, and PiD, but not CBD. They did not immunoprecipitate or immunostain tau from the control brain. Creation of potent anti-seed antibodies based on the trans-proline epitope implicates local unfolding around P301 in pathogenesis. MD2.2 and MD3.1 may also be useful for therapy and diagnosis.

Keywords

amyloid; conformation; conformation-specific antibody; prion; tau; trans-proline.

Figures
Products