The role of low-density receptor-related protein 1 (LRP1) as a competitive substrate of the amyloid precursor protein (APP) for BACE1

• Published in: Experimental neurology 2010-09, Vol.225 (1), p.85-93
• Main Authors: von Einem, Bjoern, Schwanzar, Daniel, Rehn, Florian, Beyer, Anja-Silke, Weber, Petra, Wagner, Michael, Schneckenburger, Herbert, von Arnim, Christine A.F.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease (AD); Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein (APP); Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Aspartic Acid Endopeptidases - genetics; Aspartic Acid Endopeptidases - metabolism; Beta-Site APP cleaving enzyme 1 (BACE1); Binding, Competitive - genetics; Biological and medical sciences; Cell Line; Cell Line, Tumor; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Humans; Hydrolysis; Low-density lipoprotein receptor-related protein 1 (LRP1); Medical sciences; Mice; Neurology; Protein Transport - physiology; Receptors, LDL - genetics; Receptors, LDL - metabolism; Receptors, LDL - physiology; Substrate Specificity; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumor Suppressor Proteins - physiology; Up-Regulation - genetics
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2010.05.017

Cleavage of APP by BACE1 is the first proteolytic step in the production of amyloid-beta (Aβ), which accumulates in senile plaques in Alzheimer's disease. Through its interaction with APP, the low-density receptor-related protein 1 (LRP1) enhances APP internalization. Recently, BACE1 has been shown to interact with and cleave the light chain (lc) of LRP1. Since LRP1 is known to compete with APP for cleavage by gamma-secretase, we tested the hypothesis that LRP1 also acts as a competitive substrate for β-secretase. We found that the increase in secreted APP (sAPP) mediated by over-expression of BACE1 in APP-transfected cells could be decreased by simultaneous LRP1 over-expression. Analysis by multi-spot ELISA revealed that this is due to a decrease in sAPPβ, but not sAPPα. Interaction between APP and BACE1, as measured by immunoprecipitation and fluorescence lifetime assays, was impaired by LRP1 over-expression. We also demonstrate that APP over-expression leads to decreased LRP1 association with and cleavage by BACE1. In conclusion, our data suggest that – in addition to its role in APP trafficking – LRP1 affects APP processing by competing for cleavage by BACE1.