Alzheimer's disease (AD) has been closely linked to the plaque-forming, neurotoxic peptide β-amyloid (Aβ). Aβ is derived from amyloid precursor protein (APP) through regulated-intramembrane proteolysis. APP is not only implicated in AD pathogenesis but also in important cellular processes. The type-I transmembrane protein has a large extracelluar soluble fragment known as sAPP, which is responsible for many of the proposed functions of APP. Understanding the structure of sAPP would provide a leap forward in understanding the functions of APP, as well as the mechanism of its proteolysis that causes Abeta production. Information inferred from the structure will also assist the development of novel therapeutic strategies to target AD.

Recombinant sAPP fragments were expressed and subjected to extensive crystallisation trials. Several promising crystallisation conditions were identified. Dimerisation is proposed to be a key player in mediating APP functions, including transmembrane signalling, and proteolysis. Biophysical characterisation of sAPP dimerisation has been undertaken using a variety of approaches including size-exclusion chromatography, multi-angle light scattering analysis, analytical ultracentrifugation and mass spectrometry. Several conditions have been identified to drive APP dimerisation in vitro. Our results and subsequent experiments to determine the structures of sAPP in its dimeric and monomeric forms will contribute to understanding the mechanism of dimerisation, signalling and other APP functions. This information may guide rational inhibitor design of Aβ overproduction which in turn may slow down or halt AD progression.