High-affinity antibodies specific to the core region of the tau protein exhibit diagnostic and therapeutic potential for Alzheimer’s disease

Mohammad Arastoo, Lewis Kirk Penny, Richard Andrew Lofthouse, Aya Abdallah, Anna Abrahamsson, Pietro Marini, Valeria Melis, Gernot Riedel, Charles Harrington, Claude Wischik, Andrew Porter, Soumya Palliyil* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Background
Recent advances in blood-based biomarker discovery are paving the way for simpler, more accessible diagnostic tools that can detect early signs of Alzheimer’s disease (AD). Recent successes in the development of amyloid-targeting immunotherapy approaches mark an important advancement in providing new options for the treatment of AD. We have developed a set of high-affinity monoclonal antibodies (mAbs) to tau protein that have the potential as tools for diagnosis and treatment of AD.
Methods
Sheep were immunised with either full-length tau (1-441) or truncated paired helical filament (PHF)-core tau (297–391). A stringent bio-panning and epitope selection strategy, with a particular focus directed to epitopes within the disease-relevant PHF-core tau, was used to identify single-chain antibodies (scAbs). These scAbs were ranked by affinity for each epitope class, with leads converted to high-affinity mAbs. These antibodies and their potential utility were assessed by their performance in tau immunoassays, as well as their ability to prevent tau aggregation and propagation. Further characterisation of these antibodies was performed by immunohistochemical staining of brain sections and immuno-gold electronmicroscopy of isolated PHFs.
Results
Our work resulted in a set of high-affinity antibodies reacting with multiple epitopes spanning the entire tau protein molecule. The tau antibodies directed against the core tau unit of the PHF inhibited pathological aggregation and seeding using several biochemical and cell assay systems. Through staining of brain sections and PHFs, the panel of antibodies revealed which tau epitopes were available, truncated, or occluded. In addition, highly sensitive immunoassays were developed with the ability to distinguish between and quantify various tau fragments.
Conclusion
This article introduces an alternative immunodiagnostic approach based on the concept of a “tauosome” – the diverse set of tau fragments present within biological fluids. The development of an antibody panel that can distinguish a range of different tau fragments provides the basis for a novel approach to potential diagnosis and monitoring of disease progression. Our results further support the notion that tau immunotherapy targeting the PHF-core needs to combine appropriate selection of both the target epitope and antibody affinity to optimise therapeutic potential.
Original languageEnglish
Article number209
Number of pages20
JournalAlzheimer's Research & Therapy
Volume16
Early online date2 Oct 2024
DOIs
Publication statusPublished - 2 Oct 2024

Bibliographical note

We would like to thank the South West Dementia Brain Bank (SWDBB) and
donors for the human brain tissue provided for this study. We would like to
acknowledge the University of Aberdeen core facilities of Microscopy and
Histology, Iain Fraser Cytometry Centre, and Proteomics for their support with
microscopy, flow cytometry and surface plasmon resonance, respectively.

Data Availability Statement

All data are provided within the manuscript or the Supplementary figures/
tables and the Supporting Information. Materials are available on reasonable
request.

Keywords

  • Alzheimer’s disease
  • Tauopathy
  • Tau protein
  • Paired helical filament
  • Monoclonal antibody
  • Diagnostic
  • Therapy
  • Immunotherapy

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