title: Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta.
abstract: Cerebral deposition of beta-amyloid (Abeta) peptides is a pathological hallmark of Alzheimer disease. Intramembranous proteolysis of amyloid precursor protein by a multiprotein gamma-secretase complex generates Abeta. Previously, it was reported that CD147, a glycoprotein that stimulates production of matrix metalloproteinases (MMPs), is a subunit of gamma-secretase and that the levels of secreted Abeta inversely correlate with CD147 expression. Here, we show that the levels and localization of CD147 in fibroblasts, as well as postnatal expression and distribution in brain, are distinct from those of integral gamma-secretase subunits. Notably, we show that although depletion of CD147 increased extracellular Abeta levels in intact cells, membranes isolated from CD147-depleted cells failed to elevate Abeta production in an in vitro gamma-secretase assay. Consistent with an extracellular source that modulates Abeta metabolism, synthetic Abeta was degraded more rapidly in the conditioned medium of cells overexpressing CD147. Moreover, modulation of CD147 expression had no effect on epsilon-site cleavage of amyloid precursor protein and Notch1 receptor. Collectively, our results demonstrate that CD147 modulates Abeta levels not by regulating gamma-secretase activity, but by stimulating extracellular degradation of Abeta. In view of the known function of CD147 in MMP production, we postulate that CD147 expression influences Abeta levels by an indirect mechanism involving MMPs that can degrade extracellular Abeta.
authors.affiliation: Department of Neurobiology and Neurology, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Kulandaivelu S
authors.initials: KS
authors.lastname: Vetrivel
authors.forename: Xulun
authors.initials: X
authors.lastname: Zhang
authors.forename: Xavier
authors.initials: X
authors.lastname: Meckler
authors.forename: Haipeng
authors.initials: H
authors.lastname: Cheng
authors.forename: Sungho
authors.initials: S
authors.lastname: Lee
authors.forename: Ping
authors.initials: P
authors.lastname: Gong
authors.forename: Kryslaine O
authors.initials: KO
authors.lastname: Lopes
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Ke-Jie
authors.initials: KJ
authors.lastname: Yin
authors.forename: Jin-Moo
authors.initials: JM
authors.lastname: Lee
authors.forename: Angèle T
authors.initials: AT
authors.lastname: Parent
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
authors.forename: Sangram S
authors.initials: SS
authors.lastname: Sisodia
authors.forename: Gopal
authors.initials: G
authors.lastname: Thinakaran
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; C497886:BSG protein, human; C497887:Bsg protein, mouse; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D051926:Basigin; D053829:Amyloid Precursor Protein Secretases; D020782:Matrix Metalloproteinases