Low density lipoprotein receptor-related protein (LRP) interacts with presenilin 1 and is a competitive substrate of the amyloid precursor protein (APP) for γ-secretase

Abstract

Presenilin 1 (PS1) is a critical component of the γ-secretase complex, which is involved in the cleavage of several substrates including the amyloid precursor protein (APP) and the Notch receptor. Recently, the low density receptor-related protein (LRP) has been shown to be cleaved by a γ-secretase-like activity. We postulated that LRP may interact with PS1 and tested its role as a competitive substrate for γ-secretase. In this report we show that LRP colocalizes and interacts with endogenous PS1 using coimmunoprecipitation and fluorescence lifetime imaging microscopy. In addition, we found that γ-secretase active site inhibitors do not disrupt the interaction between LRP and PS1, suggesting that the substrate associates with a γ-secretase docking site located in close proximity to PS1. This is analogous to APP-γ-secretase interactions. Finally, we show that LRP competes with APP for γ-secretase activity. Overexpression of a truncated LRP construct consisting of the C terminus, the transmembrane domain, and a short extracellular portion leads to a reduction in the levels of the Aβ40, Aβ42, and p3 peptides without changing the total level of APP expression. In addition, transfection with the β-chain of LRP causes an increase in uncleaved APP C-terminal fragments and a concomitant decrease in the signaling effects of the APP intracellular domain. In conclusion, LRP is a PS1 interactor and can compete with APP for γ-secretase enzymatic activity. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.