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 (Aβ), which is generated by cleavage of the Aβ protein precursor (APP) by β-
secretase (BACE-1) followed by γ-secretase. BACE-1 cleavage is limiting for the production of
Aβ, making it a particularly good drug target for the generation of inhibitors that lower Aβ. 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 Aβ 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.