Emerging Alzheimer's disease therapies: inhibition of beta-secretase

Among the approaches towards disease modifying treatment of Alzheimer’s disease blocking the initial step of the amyloid cascade, Aβ42 generation, has received most attention. Aβ42 generation requires two proteases, β- and γ-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, as β-secretase. The enzyme has been characterized in detail. The x-ray crystal structure, which is critical for rational inhibitor design, has been solved and shown to be similar to that of other pepsin family members. Our recent knockout studies show that BACE1 is critical for Aβ generation, but the knockout mice show an otherwise normal phenotype, raising the possibility that therapeutic BACE1 inhibition could be accomplished without major mechanism based toxicity. However, target-mediated toxicity of β-secretase inhibition cannot be ruled out, as long as the major substrates of this enzyme are unknown. While various peptidic β-secretase inhibitors have been published, the key challenge now is the generation of more drug-like compounds that could be developed for therapeutic purposes.