title: BRI2 protein regulates β-amyloid degradation by increasing levels of secreted insulin-degrading enzyme (IDE).
abstract: The amyloid precursor protein (APP) is one of the major proteins involved in Alzheimer disease (AD). Proteolytic cleavage of APP gives rise to amyloid-β (Aβ) peptides that aggregate and deposit extensively in the brain of AD patients. Although the increase in levels of aberrantly folded Aβ peptide is considered to be important to disease pathogenesis, the regulation of APP processing and Aβ metabolism is not fully understood. Recently, the British precursor protein (BRI2, ITM2B) has been implicated in influencing APP processing in cells and Aβ 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 Aβ metabolism. We find that overexpression of either BRI2 or ADanPP reduces extracellular Aβ by increasing levels of secreted insulin-degrading enzyme (IDE), a major Aβ-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.
authors.affiliation: Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany. ellen.kilger@uni-tuebingen.de
authors.forename: Ellen
authors.initials: E
authors.lastname: Kilger
authors.forename: Anika
authors.initials: A
authors.lastname: Buehler
authors.forename: Heidrun
authors.initials: H
authors.lastname: Woelfing
authors.forename: Sathish
authors.initials: S
authors.lastname: Kumar
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Kaeser
authors.forename: Amudha
authors.initials: A
authors.lastname: Nagarathinam
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.forename: Mathias
authors.initials: M
authors.lastname: Jucker
authors.forename: Janaky
authors.initials: J
authors.lastname: Coomaraswamy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D059748:Proteolysis; D017384:Sequence Deletion
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; C120083:ITM2B protein, human; C492300:Itm2b protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D007339:Insulysin