The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate

Christine A.F. Von Arnim, Ayae Kinoshita, Ithan D. Peltan, Michelle M. Tangredi, Lauren Herl, Bonny M. Lee, Robert Spoelgen, Tammy T. Hshieh, Sripriya Ranganathan, Frances D. Battey, Chun Xiang Liu, Brian J. Bacskai, Sanja Sever, Michael C. Irizarry, Dudley K. Strickland, Bradley T. Hyman

Research output: Contribution to journalArticlepeer-review

228 Scopus citations


BACE is a transmembrane protease with β-secretase activity that cleaves the amyloid precursor protein (APP). After BACE cleavage, APP becomes a substrate for γ-secretase, leading to release of amyloid-β peptide (Aβ), which accumulates in senile plaques in Alzheimer disease. APP and BACE are co-internalized from the cell surface to early endosomes. APP is also known to interact at the cell surface and be internalized by the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytic and signaling receptor. Using a new fluorescence resonance energy transfer (FRET)-based assay of protein proximity, fluorescence lifetime imaging (FLIM), and co-immunoprecipitation we demonstrate that the light chain of LRP interacts with BACE on the cell surface in association with lipid rafts. Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-terminal fragment, release of secreted LRP in the media and subsequent release of the LRP intracellular domain from the membrane. Taken together, these data suggest that there is a close interaction between BACE and LRP on the cell surface, and that LRP is a novel BACE substrate.

Original languageEnglish (US)
Pages (from-to)17777-17785
Number of pages9
JournalJournal of Biological Chemistry
Issue number18
StatePublished - May 6 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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