TY - JOUR
T1 - Identification of BACE2 as an avid -amyloid-degrading protease
AU - Abdul-Hay, Samer O.
AU - Sahara, Tomoko
AU - McBride, Melinda
AU - Kang, Dongcheul
AU - Leissring, Malcolm A.
N1 - Funding Information:
We thank Dr. Terrone Newberry and William Tay for providing monomeric and fibrillar Aß peptides and Drs. Todd Golde and Kevin Felsenstein for contributing the APP-AP construct. Supported by a grant from the Coins For Alzheimer’s Trust Fund to ML.
PY - 2012
Y1 - 2012
N2 - Background: Proteases that degrade the amyloid β-protein (Aβ) have emerged as key players in the etiology and potential treatment of Alzheimers disease (AD), but it is unlikely that all such proteases have been identified. To discover new A-degrading proteases (AβDPs), we conducted an unbiased, genome-scale, functional cDNA screen designed to identify proteases capable of lowering net Aβ levels produced by cells, which were subsequently characterized for Aβ-degrading activity using an array of downstream assays. Results: The top hit emerging from the screen was β-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 Aβ. BACE2 is known to be capable of lowering Aβ levels via non-amyloidogenic processing of APP. However, in vitro, BACE2 was also found to be a particularly avid ADP, with a catalytic efficiency exceeding all known AβDPs except insulin-degrading enzyme (IDE). BACE1 was also found to degrade Aβ, albeit ∼150-fold less efficiently than BACE2. A is cleaved by BACE2 at three peptide bondsPhe19-Phe20, Phe20-Ala21, and Leu34-Met35with 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 AβDPs, 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 AβDP. 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.
AB - Background: Proteases that degrade the amyloid β-protein (Aβ) have emerged as key players in the etiology and potential treatment of Alzheimers disease (AD), but it is unlikely that all such proteases have been identified. To discover new A-degrading proteases (AβDPs), we conducted an unbiased, genome-scale, functional cDNA screen designed to identify proteases capable of lowering net Aβ levels produced by cells, which were subsequently characterized for Aβ-degrading activity using an array of downstream assays. Results: The top hit emerging from the screen was β-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 Aβ. BACE2 is known to be capable of lowering Aβ levels via non-amyloidogenic processing of APP. However, in vitro, BACE2 was also found to be a particularly avid ADP, with a catalytic efficiency exceeding all known AβDPs except insulin-degrading enzyme (IDE). BACE1 was also found to degrade Aβ, albeit ∼150-fold less efficiently than BACE2. A is cleaved by BACE2 at three peptide bondsPhe19-Phe20, Phe20-Ala21, and Leu34-Met35with 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 AβDPs, 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 AβDP. 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.
KW - -site APP-cleaving enzyme-2
KW - Alzheimer disease
KW - Amyloid-β-protein
KW - Functional screen
KW - Gene therapy
KW - Protease
KW - Proteolytic degradation
KW - β-site APP-cleaving enzyme-1
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UR - http://www.scopus.com/inward/citedby.url?scp=84867583311&partnerID=8YFLogxK
U2 - 10.1186/1750-1326-7-46
DO - 10.1186/1750-1326-7-46
M3 - Article
C2 - 22986058
AN - SCOPUS:84867583311
SN - 1750-1326
VL - 7
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 46
ER -