BRI2 Protein Regulates β-Amyloid Degradation by Increasing Levels of Secreted Insulin-degrading Enzyme (IDE)

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 (A beta) peptides that aggregate and deposit extensively in the brain of AD patients. Although the increase in levels of aberrantly folded A beta peptide is considered to be important to disease pathogenesis, the regulation of APP processing and A beta metabolism is not fully understood. Recently, the British precursor protein (BRI2, ITM2B) has been implicated in influencing APP processing in cells and A beta 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 A beta metabolism. We find that overexpression of either BRI2 or ADanPP reduces extracellular A beta by increasing levels of secreted insulin-degrading enzyme (IDE), a major A beta-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.