Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta.
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.
Vetrivel
Kulandaivelu S
KS
Department of Neurobiology and Neurology, The University of Chicago, Chicago, Illinois 60637, USA.
Zhang
Xulun
X
Meckler
Xavier
X
Cheng
Haipeng
H
Lee
Sungho
S
Gong
Ping
P
Lopes
Kryslaine O
KO
Chen
Ying
Y
Iwata
Nobuhisa
N
Yin
Ke-Jie
KJ
Lee
Jin-Moo
JM
Parent
Angèle T
AT
Saido
Takaomi C
TC
Li
Yue-Ming
YM
Sisodia
Sangram S
SS
Thinakaran
Gopal
G
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
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