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.
Highlights
The biogenesis, maturation, stability, and steady-state levels of ␥-secretase complex subunits are codependent
Stability of CD147 Is Not Affected in the Absence of ␥-Secretase Core Components—If CD147 is a bona fide component of ␥-secretase, one would anticipate that the behavior of the polypeptide with respect to regulated stability would be similar to that already established for other core components of the complex, i.e. that the stability and maturation of ␥-secretase subunits are co-regulated
The stability of CD147 is not co-regulated in a manner such as PS1, nicastrin, APH1, and PEN-2, indicating that CD147 is unlikely to be an integral subunit of the ␥-secretase complex
Summary
A, -amyloid; APP, amyloid precursor protein; PS, presenilin; NTF, N-terminal fragment; CTF, C-terminal fragment; siRNA, small interfering RNA; ER, endoplasmic reticulum; MMP, matrix metalloproteinase; MEFs, mouse embryonic fibroblasts; CHAPSO, 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid; DRM, detergent-resistant membrane; MOPS, 4-morpholinepropanesulfonic acid; ELISA, enzyme-linked immunosorbent assay; WT, wild-type; AICD, APP intracellular domain; NICD, Notch intracellular domain; Tricine, N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine. CD147 ( called EMMPRIN (extracellular matrix metalloproteinase inducer), Basigin, neurothelin, and M6 leukocyte activation antigen) is a multifunctional cell-surface type I transmembrane protein that stimulates matrix metalloproteinase (MMP) secretion [18]. We found evidence for enhanced degradation of A in medium conditioned by cells overexpressing CD147, suggesting the potential involvement of CD147-induced MMP secreted forms in modulating extracellular A levels. Consistent with this indirect mechanism, the absence of PS1 and nicastrin has no effect on CD147 stability and subcellular localization, and CD147 expression fails to influence ␥-secretase subunit expression and lipid raft association. A distinct expression pattern and distribution of CD147 and nicastrin in brain further support our view that CD147 regulates extracellular A levels via mechanisms independent of ␥-secretase processing of APP
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