Human beta-secretase and Alzheimer's disease

Alzheimer's disease (AD) is a huge unmet medical need. Studies of the brain pathology and genetics of familial forms of AD have led to the amyloid cascade hypothesis, stating that Abeta42, a proteolytic breakdown product of the large amyloid precursor protein, plays an early and critical role in AD pathogenesis. Abeta42 generation requires two proteases, beta- and gamma-secretase, and inhibition of these enzymes is a key focus of AD drug development. Progress in this area has been slow because these enzymes were not identified. Using an expression cloning strategy we have identified a novel membrane bound aspartic protease, BACE1 and demonstrated that it exhibits all known properties of beta-secretase. The enzyme has been characterised in detail. The crystal structure, which is critical for rational inhibitor design, has been solved and shown to be very similar to that of other pepsin family members. Our most recent BACE1 knockout studies show that BACE1 is critical for Abeta generation; however the knockout mice show an otherwise normal phenotype, raising the possibility that therapeutic BACE1 inhibition could be accomplished without major mechanism based toxicity.