Identification of BACE2 as an avid β-amyloid-degrading protease

Background: Proteases that degrade the amyloid beta-protein (A beta) have emerged as key players in the etiology and potential treatment of Alzheimer's disease (AD), but it is unlikely that all such proteases have been identified. To discover new A beta-degrading proteases (A beta DPs), we conducted an unbiased, genome-scale, functional cDNA screen designed to identify proteases capable of lowering net A beta levels produced by cells, which were subsequently characterized for A beta-degrading activity using an array of downstream assays. Results: The top hit emerging from the screen was beta-site amyloid precursor protein-cleaving enzyme 2 (BACE2), a rather unexpected finding given the well-established role of its close homolog, BACE1, in the production of A beta. BACE2 is known to be capable of lowering A beta levels via non-amyloidogenic processing of APP. However, in vitro, BACE2 was also found to be a particularly avid A beta DP, with a catalytic efficiency exceeding all known A beta DPs except insulin-degrading enzyme (IDE). BACE1 was also found to degrade A beta, albeit similar to 150-fold less efficiently than BACE2. A beta is cleaved by BACE2 at three peptide bonds Phe19-Phe20, Phe20-Ala21, and Leu34-Met35 with the latter cleavage site being the initial and principal one. BACE2 overexpression in cultured cells was found to lower net A beta levels to a greater extent than multiple, well-established A beta DPs, including neprilysin (NEP) and endothelin-converting enzyme-1 (ECE1), while showing comparable effectiveness to IDE. Conclusions: This study identifies a new functional role for BACE2 as a potent A beta DP. Based on its high catalytic efficiency, its ability to degrade A beta intracellularly, and other characteristics, BACE2 represents a particulary strong therapeutic candidate for the treatment or prevention of AD.