Antagonistic Effects of β-Site Amyloid Precursor Protein-cleaving Enzymes 1 and 2 on β-Amyloid Peptide Production in Cells*

The deposition of extracellular β-amyloid peptide (Aβ) in the brain is a pathologic feature of Alzheimer's disease. The β-site amyloid precursor protein cleaving enzyme 1 (BACE1), an integral membrane aspartyl protease responsible for cleavage of amyloid precursor protein (APP) at the β-site, promotes Aβ production. A second integral membrane aspartyl protease related to BACE1, referred to as β-site amyloid precursor protein cleaving enzyme 2 (BACE2) has also been demonstrated to cleave APP at the β-cleavage site in transfected cells. The role of endogenous BACE2 in Aβ production remains unresolved. We investigated the role of endogenous BACE2 in Aβ production in cells by selective inactivation of its transcripts using RNA interference. We are able to reduce steady state levels for mRNA for each enzyme by >85%, and protein amounts by 88–94% in cells. Selective inactivation of BACE1 by RNA interference results in decreased β-cleaved secreted APP and Aβ peptide secretion from cells, as expected. Selective inactivation of BACE2 by RNAi results in increased β-cleaved secreted APP and Aβ peptide secretion from cells. Simultaneous targeting of both enzymes by RNA interference does not have any net effect on Aβ released from cells. Our observations of changes in APP metabolism and Aβ are consistent with a role of BACE2 in suppressing Aβ production in cells that co-express both enzymes.

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