The role of low-density receptor-related protein 1 (LRP1) as a competitive substrate of the amyloid precursor protein (APP) for BACE1.
Cleavage of APP by BACE1 is the first proteolytic step in the production of amyloid-beta (Abeta), 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 beta-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 sAPPbeta, but not sAPPalpha. 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.
von Einem
Bjoern
B
Dept. of Neurology, Ulm University, Albert Einstein Allee 11, 89081 Ulm, Germany. christine.arnim@uni-ulm.de
Schwanzar
Daniel
D
Rehn
Florian
F
Beyer
Anja-Silke
AS
Weber
Petra
P
Wagner
Michael
M
Schneckenburger
Herbert
H
von Arnim
Christine A F
CA
D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001667:Binding, Competitive / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D006868:Hydrolysis; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D021381:Protein Transport / Q000502:physiology; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse