Evidence that CD147 modulation of β-amyloid (Aβ) levels is mediated by extracellular degradation of secreted Aβ

Cerebral deposition of beta-amyloid (A beta)peptides is a pathological hallmark of Alzheimer disease. Intramembranous proteolysis of amyloid precursor protein by a multiprotein gamma-secretase complex generates A beta. 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 A beta 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 A beta levels in intact cells, membranes isolated from CD147-depleted cells failed to elevate A beta production in an in vitro gamma-secretase assay. Consistent with an extracellular source that modulates A beta metabolism, synthetic A beta 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 A beta levels not by regulating gamma-secretase activity, but by stimulating extracellular degradation of A beta. In view of the known function of CD147 in MMP production, we postulate that CD147 expression influences A beta levels by an indirect mechanism involving MMPs that can degrade extracellular A beta.