Enzyme That Fights Alzheimer’s Disease

Samer O Abdul-Hay, Tomoko Sahara, Melinda McBride, Dongcheul Kang and Malcolm A Leissring

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

Molecular Neurodegeneration 2012, 7:46 doi:

Published: 17 September 2012

Abstract (provisional)

Background

Proteases that degrade the amyloid SZ-protein (ASZ) 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 discovered. To discover new ASZ-degrading proteases (ASZDPs), we conducted an unbiased, genome-scale, functional cDNA screen designed to identify proteases capable of lowering net ASZ levels produced by cells, which were subsequently characterized for ASZ-degrading activity using an array of downstream assays.

Results

The top hit emerging from the screen was SZ-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 ASZ. BACE2 is known to be capable of lowering ASZ levels via non-amyloidogenic processing of APP. However, in vitro, BACE2 was also found to be a particularly avid ASZDP, with a catalytic efficiency exceeding all known ASZDPs except insulin-degrading enzyme (IDE). BACE1 was also found to degrade ASZ, albeit ~150-fold less efficiently than BACE2. ASZ 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 ASZ levels to a greater extent than multiple, well-established ASZDPs, including neprilysin (NEP) and endothelinconverting enzyme-1 (ECE1), while showing comparable effectiveness to IDE.

Conclusions

This study identifies a new functional role for BACE2 as a potent ASZDP. Based on its high catalytic efficiency, its ability to degrade ASZ intracellularly, and other characteristics, BACE2 represents a particulary strong therapeutic candidate for the treatment or prevention of AD.