07 Dec 2001

Dr. Citron began his presentation by emphasizing that the cerebral deposition of Aβ is an early and critical feature of AD, and that Aβ is released from APP by the sequential action of two proteases, β-secretase and γ-secretase. Thus, Dr. Citron noted that these proteases are prime targets for therapeutic intervention, and for this reason he and his colleagues recently cloned a novel aspartic protease, BACE1, with all the known properties of the β-secretase that in part is responsible for the release of Aβ from APP. Dr. Citron then briefly summarized how he and his colleagues conducted studies that led to the initial identification of BACE1 and he also described some of its properties. He then went on to review the crystal structure of BACE1 and data from his studies of BACE1 knockout mice that he and his colleagues recently generated. This presentation concluded with a discussion of the pros and cons of BACE1 inhibition as a therapeutic strategy compared to other amyloid therapies. While lively, this discussion was largely theoretical since, compared to the other therapies that currently target Aβ amyloid deposits, there is little published preclinical data from studies in model systems upon which to base solid predictions on there relative merits of the different approaches to the therapy of AD.—John Trojanowski