The AβCC peptide™ technology is a great tool for improving the productivity in the field of Alzheimer’s disease therapeutics. The technology effectively solves the problem associated with developing therapeutics against the metastable soluble amyloid-β (Aβ) toxins (oligomers/protofibrils) that play a central role in the disease process.
In Alzheimer’s disease, a protein fragment denoted Aβ42 progressively accumulates in the brain where it eventually starts to aggregate into soluble structures (denoted “oligomers”) and larger insoluble fibril structures that are found in amyloid plaques (see figure below). Several research groups have shown that oligomeric Aβ42 is particularly damaging to brain cells when compared to unaggregated (monomeric) and fibrillar forms. Oligomers are therefore primary therapeutic targets.
A recently published structural model of these oligomers (available here) demonstrates that they are structurally distinct from monomers and fibrils, and that they therefore can be targeted specifically. In an in vitro setting, however, the oligomeric forms of Aβ are notoriously elusive because Aβ is in a continuous equilibrium with different soluble and insoluble aggregated states. The result is a heterogeneous mix of different forms of the peptide that continuously shifts towards the end state: the inert insoluble fibrils. This poses serious problems when oligomers are to be used as analytes in research. Importantly, it precludes all uses of Aβ oligomers as components of therapeutic vaccines.
The AβCC peptide™ technology solves the problem of metastability and heterogeneity by conformational restriction of the oligomers. A disulfide bond prevents the conformational switch required for fibril formation. In consequence, Aβ42CC accumulates as stable oligomers with β secondary structure which are unable to form fibrils even under strong fibril-forming conditions. With the AβCC peptide™ technology, Alzinova can thus isolate large amounts of mimetic Aβ42 oligomers which are used as antigens in the development of immunotherapy.