Beta-Secretase: Structure, Function, and Evolution

The most popular current hypothesis is that Alzheimer's disease (AD) is caused by aggregates of the amyloid peptide (A beta) which is generated by cleavage of the A beta protein precursor (APP) by beta-secretase (BACE-1) followed by gamma-secretase. BACE-1 cleavage is limiting for the production of A beta making it a particularly good drug target for the generation of inhibitors that lower A beta. A landmark discovery in AD was the identification of BACE-1 (a.k.a. Memapsin-2) as a novel class of type I transmembrane aspartic protease. Although BACE-2, a homologue of BACE-1, was quickly identified, follow up studies using knockout mice demonstrated that BACE-1 was necessary and sufficient for most neuronal A beta generation. Despite the importance of BACE-1 as a drug target, development has been slow due to the incomplete understanding of its function and regulation and the difficulties in developing a brain penetrant drug that can specifically block its large catalytic pocket. This review summarizes the biological properties of BACE-1 and attempts to use phylogenetic perspectives to understand its function. The article also addresses the challenges in discovering a selective drug-like molecule targeting novel mechanisms of BACE-1 regulation.