Growing evidence suggests that soluble forms of Aβ are key to AD progression and may represent attractive therapeutic targets as they inhibit long-term potentiation, trigger synaptic plasticity and synapse loss.
While amyloid plaques represent typical hallmarks of AD, soluble oligomers have been shown to better correlate with the clinical pathology. 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.Īlzheimer’s disease (AD) is a progressive neurodegenerative condition characterised by the presence of extracellular deposits of the amyloid-beta (Aβ) protein. Treating both models with the humanised version of the TAP01 antibody had similar positive effects. 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.
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. 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 previously identified a murine antibody (TAP01), which binds specifically to soluble, non-plaque N-truncated Aβ species. 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. One of the hallmarks of Alzheimer’s disease (AD) are deposits of amyloid-beta (Aβ) protein in amyloid plaques in the brain.
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