title: Systematic evaluation of candidate ligands regulating ectodomain shedding of amyloid precursor protein.
abstract: Despite intense interest in the proteolysis of the β-Amyloid Precursor Protein (APP) in Alzheimer's disease, how the normal processing of this type I receptor-like glycoprotein is physiologically regulated remains ill-defined. In recent years, several candidate protein ligands for APP, including F-spondin, Reelin, β1 Integrin, Contactins, Lingo-1, and Pancortin, have been reported. However, a cognate ligand for APP that regulates its processing by α- or β-secretase has yet to be widely confirmed in multiple laboratories. Here, we developed new assays in an effort to confirm a role for one or more of these candidate ligands in regulating APP ectodomain shedding in a biologically relevant context. A comprehensive quantification of APPsα and APPsβ, the immediate products of secretase processing, in both non-neuronal cell lines and primary neuronal cultures expressing endogenous APP yielded no evidence that any of these published candidate ligands stimulate ectodomain shedding. Rather, Reelin, Lingo-1, and Pancortin-1 emerged as the most consistent ligands for significantly inhibiting ectodomain shedding. These findings led us to conduct further detailed analyses of the interactions of Reelin and Lingo-1 with APP.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Rice
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Young-Pearse
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C482293:LINGO1 protein, human; D008024:Ligands; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; C081451:olfactomedin; D053829:Amyloid Precursor Protein Secretases; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases