CD147 is a regulatory subunit of the γ-secretase complex in Alzheimer's disease amyloid β-peptide production

摘要

γ-Secretase is a membrane protein complex that cleaves the β-amyloid precursor protein (APP) within the transmembrane region, after prior processing by β-secretase, producing amyloid β-peptides Aβ_(40) and Aβ_(42). Errant production of Aβ-peptides that substantially increases Aβ_(42) production has been associated with the formation of amyloid plaques in Alzheimer's disease patients. Biophysical and genetic studies indicate that presenilin-1, which contains the proteolytic active site, and three other membrane proteins [nicastrin, anterior pharynx defective-1 (APH-1), and pre-senilin enhancer-2 (PEN-2)] are required to form the core of the active γ-secretase complex. Here, we report the purification of the native γ-secretase complexes from HeLa cell membranes and the identification of an additional γ-secretase complex subunit, CD147, a transmembrane glycoprotein with two lg-like domains. The presence of this subunit as an integral part of the complex itself was confirmed through coimmunoprecipitation studies of the purified protein from HeLa cells and of solubilized complexes from other cell lines such as neural cell HCN-1A and HEK293. Depletion of CD147 by RNA interference was found to increase the production of Aβ peptides without changing the expression level of the other γ-secretase components or APP substrates whereas CD147 overexpression had no statistically significant effect on Aβ-peptide production, other γ-secretase components or APP substrates, indicating that the presence of the CD147 subunit within the γ-secretase complex down-modulates the production of Aβ-peptides.