| First Author | Kilger E | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 43 | Pages | 37446-57 |
| PubMed ID | 21873424 | Mgi Jnum | J:177577 |
| Mgi Id | MGI:5295513 | Doi | 10.1074/jbc.M111.288373 |
| Citation | Kilger E, et al. (2011) BRI2 Protein Regulates {beta}-Amyloid Degradation by Increasing Levels of Secreted Insulin-degrading Enzyme (IDE). J Biol Chem 286(43):37446-57 |
| abstractText | The amyloid precursor protein (APP) is one of the major proteins involved in Alzheimer disease (AD). Proteolytic cleavage of APP gives rise to amyloid-beta (Abeta) peptides that aggregate and deposit extensively in the brain of AD patients. Although the increase in levels of aberrantly folded Abeta peptide is considered to be important to disease pathogenesis, the regulation of APP processing and Abeta metabolism is not fully understood. Recently, the British precursor protein (BRI2, ITM2B) has been implicated in influencing APP processing in cells and Abeta deposition in vivo. Here, we show that the wild type BRI2 protein reduces plaque load in an AD mouse model, similar to its disease-associated mutant form, ADan precursor protein (ADanPP), and analyze in more detail the mechanism of how BRI2 and ADanPP influence APP processing and Abeta metabolism. We find that overexpression of either BRI2 or ADanPP reduces extracellular Abeta by increasing levels of secreted insulin-degrading enzyme (IDE), a major Abeta-degrading protease. This effect is also observed with BRI2 lacking its C-terminal 23-amino acid peptide sequence. Our results suggest that BRI2 might act as a receptor protein that regulates IDE levels that in turn influences APP metabolism in a previously unrecognized way. Targeting the regulation of IDE may be a promising therapeutic approach to sporadic AD. |
