7ow1

Publication Abstract from PubMed

One of the hallmarks of Alzheimer's disease (AD) are deposits of amyloid-beta (Abeta) protein in amyloid plaques in the brain. The Abeta peptide exists in several forms, including full-length Abeta1-42 and Abeta1-40 - and the N-truncated species, pyroglutamate Abeta3-42 and Abeta4-42, 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 Abeta species. By solving crystal structures for TAP01 family antibodies bound to pyroglutamate Abeta3-14, we identified a novel pseudo beta-hairpin structure in the N-terminal region of Abeta and show that this underpins its unique binding properties. We engineered a stabilised cyclic form of Abeta1-14 (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 Abeta, which offers new routes for active and passive immunisation against AD.

Discovery of a novel pseudo beta-hairpin structure of N-truncated amyloid-beta for use as a vaccine against Alzheimer's disease.,Bakrania P, Hall G, Bouter Y, Bouter C, Beindorff N, Cowan R, Davies S, Price J, Mpamhanga C, Love E, Matthews D, Carr MD, Bayer TA Mol Psychiatry. 2022 Feb;27(2):840-848. doi: 10.1038/s41380-021-01385-7. Epub , 2021 Nov 15. PMID:34776512^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.