Antagonistic effects of beta-site amyloid precursor protein-cleaving enzymes 1 and 2 on beta-amyloid peptide production in cells.
J Biol Chem
; 278(34): 31512-20, 2003 Aug 22.
Article
in En
| MEDLINE
| ID: mdl-12801932
ABSTRACT
The deposition of extracellular beta-amyloid peptide (A beta) 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 A beta 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 A beta production remains unresolved. We investigated the role of endogenous BACE2 in A beta 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 A beta peptide secretion from cells, as expected. Selective inactivation of BACE2 by RNAi results in increased beta-cleaved secreted APP and A beta peptide secretion from cells. Simultaneous targeting of both enzymes by RNA interference does not have any net effect on A beta released from cells. Our observations of changes in APP metabolism and A beta are consistent with a role of BACE2 in suppressing A beta production in cells that co-express both enzymes.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Processing, Post-Translational
/
Amyloid beta-Peptides
/
Aspartic Acid Endopeptidases
Limits:
Humans
Language:
En
Journal:
J Biol Chem
Year:
2003
Document type:
Article
Affiliation country:
United States