Polarized secretion of beta-amyloid precursor protein and amyloid beta-peptide in MDCK cells.

摘要

The beta-amyloid precursor protein (beta APP) is awidely expressed integral membrane protein that is proteolytically processed toyield several secreted derivatives, including soluble APP (APPs), the 4-kDaamyloid beta-peptide (A beta), and a related 3-kDa peptide (p3). To understandbeta APP trafficking and processing, we analyzed the sorting of beta APP inMadin-Darby canine kidney (MDCK) cells, an epithelial cell known to possessphysiologically distinct apical and basolateral plasma membranes. Processing ofbeta APP resulted in highly polarized secretion of APPs. More than 90% of APPswas detected in the basolateral compartment, and less than 10% was found in theapical compartment. This was associated with a preferential localization of betaAPP on the basolateral cell surface. Activation of protein kinase C, which isknown to enhance the secretion of APPs, did not change the polarity of APPsrelease but significantly increased the amount secreted. A beta and p3 peptideswere also secreted predominantly basolaterally. In addition, MDCK cells secreteda truncated form of A beta beginning at Arg-5. These data show that theproteolytic processing products of beta APP undergo polarized secretion.Moreover, the results suggest that the amyloidogenic A beta peptide is generatedfollowing the polarized sorting of beta APP. The polarized basolateral secretionof A beta in these epithelial cells provides a potential mechanism for theaccumulation of A beta in the abluminal basement membrane of brain microvesselsduring Alzheimer disease.