Antagonistic effects of β-site amyloid precursor protein-cleaving enzymes 1 and 2 on β-amyloid peptide production in cells

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