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

• Published in: Molecular neurodegeneration Vol. 7; no. 1; p. 46
• Main Authors: Abdul-Hay, Samer O, Sahara, Tomoko, McBride, Melinda, Kang, Dongcheul, Leissring, Malcolm A
• Format: Journal Article
• Language: English
• Published: 01-01-2012
• Subjects: Alzheimer's disease; Amyloid; Amyloid precursor protein; beta -Site APP cleaving enzyme 1; beta -Site APP cleaving enzyme 2; Enzymes; Etiology; Genomes; Insulysin; Neprilysin; Neurodegenerative diseases; Proenzymes; Proteinase
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/1750-1326-7-46

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