Identification of BACE2 as an avid -amyloid-degrading protease

Background Proteases that degrade the amyloid -protein (A ) 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 -degrading proteases (A DPs), we conducted an unbiased, genome-scale, functional cDNA screen designed to identify proteases capable of lowering net A levels produced by cells, which were subsequently characterized for A -degrading activity using an array of downstream assays. Results The top hit emerging from the screen was -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 . BACE2 is known to be capable of lowering A levels via non-amyloidogenic processing of APP. However, in vitro, BACE2 was also found to be a particularly avid A DP, with a catalytic efficiency exceeding all known A DPs except insulin-degrading enzyme (IDE). BACE1 was also found to degrade A , albeit ~150-fold less efficiently than BACE2. A 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 levels to a greater extent than multiple, well-established A 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 DP. Based on its high catalytic efficiency, its ability to degrade A intracellularly, and other characteristics, BACE2 represents a particulary strong therapeutic candidate for the treatment or prevention of AD.