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Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer’s disease

Molecular Psychiatry volume 27, pages 840–848 (2022)Cite this article

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Abstract

One of the hallmarks of Alzheimer’s disease (AD) are deposits of amyloid-beta (Aβ) protein in amyloid plaques in the brain. The Aβ peptide exists in several forms, including full-length Aβ1-42 and Aβ1-40 – and the N-truncated species, pyroglutamate Aβ3-42 and Aβ4-42, which appear to play a major role in neurodegeneration. We previously identified a murine antibody (TAP01), which binds specifically to soluble, non-plaque N-truncated Aβ species. By solving crystal structures for TAP01 family antibodies bound to pyroglutamate Aβ3-14, we identified a novel pseudo β-hairpin structure in the N-terminal region of Aβ and show that this underpins its unique binding properties. We engineered a stabilised cyclic form of Aβ1-14 (N-Truncated Amyloid Peptide AntibodieS; the ‘TAPAS’ vaccine) and showed that this adopts the same 3-dimensional conformation as the native sequence when bound to TAP01. Active immunisation of two mouse models of AD with the TAPAS vaccine led to a striking reduction in amyloid-plaque formation, a rescue of brain glucose metabolism, a stabilisation in neuron loss, and a rescue of memory deficiencies. Treating both models with the humanised version of the TAP01 antibody had similar positive effects. Here we report the discovery of a unique conformational epitope in the N-terminal region of Aβ, which offers new routes for active and passive immunisation against AD.

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Fig. 1: Structure of the TAP01-Aβ pE3-14 complex.
Fig. 2: Active and passive immunisation reduced amyloid plaque load in 5XFAD mice.
Fig. 3: Active immunisation of 5XFAD mice normalised brain glucose metabolism.
Fig. 4: Active and passive immunisation in Tg4-42 mice rescued on neuron number and on spatial reference memory.

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Acknowledgements

We thank Helen Payne for performing the ELISA for screening the sera from the 5XFAD mice and the protein production team at LifeArc for the generation of recombinant antibody material for in vivo studies. We thank Max Ueberück for performing immunostaining and plaque load analysis. This study was supported by a structural biology research partnership between LifeArc and Prof. Carr’s group at the University of Leicester.

Funding

German Research Foundation grant INST 335/454-1 FUGG (NB).

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Author notes

  1. David Matthews

    Present address: Mogrify, Bio-Innovation Centre, Cambridge Science Park, Cambridge, UK

  2. These authors contributed equally: Preeti Bakrania, Gareth Hall, Yvonne Bouter.

Authors and Affiliations

  1. LifeArc, Centre for Therapeutics Discovery, Open Innovation Campus, Stevenage, UK

    Preeti Bakrania, Sarah Davies, Jemma Price, Chido Mpamhanga, Elizabeth Love & David Matthews

  2. Leicester Institute of Structural and Chemical Biology and Department of Molecular and Cell Biology, Henry Wellcome Building, University of Leicester, Leicester, UK

    Gareth Hall, Richard Cowan & Mark D. Carr

  3. Department of Psychiatry and Psychotherapy, University Medical Center Göttingen (UMG), Georg-August-University, Göttingen, Germany

    Yvonne Bouter & Thomas A. Bayer

  4. Department of Nuclear Medicine, University Medical Center Göttingen (UMG), Georg-August-University, Göttingen, Germany

    Caroline Bouter

  5. Berlin Experimental Radionuclide Imaging Center (BERIC), Charité-Universitätsmedizin Berlin, Berlin, Germany

    Nicola Beindorff

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Contributions

Conceptualisation: MDC, PB, TAB, DM. Methodology: CM, GH, MDC, PB, RC, EL, HP, JP, SD, CB, NB, YB. Investigation: GH, MDC, DM, PB, YB, TAB. Visualisation: GH, MDC, PB, TAB. Project administration: DM, PB. Supervision: GH, MDC, DM, PB, TAB. Writing – original draft: GH, MDC, PB, TAB. Writing – review & editing: GH, MDC, PB, TAB.

Corresponding authors

Correspondence to Preeti Bakrania, Mark D. Carr or Thomas A. Bayer.

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LifeArc and University Medicine Goettingen hold patents on the project.

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Bakrania, P., Hall, G., Bouter, Y. et al. Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer’s disease. Mol Psychiatry 27, 840–848 (2022). https://doi.org/10.1038/s41380-021-01385-7

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