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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

DOI: 10.1038/s41380-021-01385-7 DOI Help

Authors: Preeti Bakrania (LifeArc, Centre for Therapeutics Discovery) , Gareth Hall (University of Leicester) , Yvonne Bouter (University Medical Center Göttingen (UMG), Georg-August-University) , Caroline Bouter (University Medical Center Göttingen (UMG), Georg-August-University) , Nicola Beindorff (Berlin Experimental Radionuclide Imaging Center (BERIC), Charité-Universitätsmedizin Berlin) , Richard Cowan (University of Leicester) , Sarah Davies (LifeArc, Centre for Therapeutics Discovery) , Jemma Price (LifeArc, Centre for Therapeutics Discovery) , Chido Mpamhanga (LifeArc, Centre for Therapeutics Discovery) , Elizabeth Love (LifeArc, Centre for Therapeutics Discovery) , David Matthews (LifeArc, Centre for Therapeutics Discovery) , Mark D. Carr (University of Leicester) , Thomas A. Bayer (University Medical Center Göttingen (UMG), Georg-August-University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Psychiatry , VOL 46

State: Published (Approved)
Published: November 2021

Open Access Open Access

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.

Journal Keywords: Alzheimer's Disease

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Other Facilities: ID30B at ESRF

Added On: 21/11/2021 16:08

Documents:
s41380-021-01385-7.pdf

Discipline Tags:

Vaccines Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)