ArticleMolecular psychiatry2022
Discovery of a novel pseudo β-hairpin structure of N-truncated amyloid-β for use as a vaccine against Alzheimer's disease.
Article in Molecular psychiatry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 24 citations in OpenAlex.
- The concentric β-barrel hypothesis for amyloids: Models of soluble and transmembrane amyloid-β42 oligomers and channels composed of identical subunits and GM1 gangliosides.bioRxiv : the preprint server for biology · 2026Article
- Review
- Alzheimer's disease: from early pathogenesis to novel therapeutic approaches.Metabolic brain disease · 2024Review
- Engineered Antibodies to Improve Efficacy against Neurodegenerative Disorders.International journal of molecular sciences · 2024Review
- An electrostatic cluster guides Aβ40 fibril formation in sporadic and Dutch-type cerebral amyloid angiopathy.Journal of structural biology · 2024Article
- A turn for the worse: Aβ β-hairpins in Alzheimer's disease.Bioorganic & medicinal chemistry · 2024Review
- Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2024Article
- New perspectives on sex differences in learning and memory.Trends in endocrinology and metabolism: TEM · 2023Review
- Crystal structures of the human IgD Fab reveal insights into CMolecular immunology · 2023Article
- Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer's Disease.International journal of molecular sciences · 2023Article
- Current Peptide Vaccine and Immunotherapy Approaches Against Alzheimer's Disease.Peptide science (Hoboken, N.J.) · 2023Article
- Insights into Cerebral Amyloid Angiopathy Type 1 and Type 2 from Comparisons of the Fibrillar Assembly and Stability of the Aβ40-Iowa and Aβ40-Dutch Peptides.Biochemistry · 2022Article
- Donanemab detects a minor fraction of amyloid-β plaques in post-mortem brain tissue of patients with Alzheimer's disease and Down syndrome.Acta neuropathologica · 2022Article
- Immunotherapy for Alzheimer's disease: targeting β-amyloid and beyond.Translational neurodegeneration · 2022Review
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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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