CELL-SURFACE APP751 FORMS COMPLEXES WITH PROTEASE NEXIN-2 LIGANDS ANDIS INTERNALIZED VIA THE LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN (LRP)

The secreted isoforms of the amyloid precursor protein (APP) that cont ain the Kunitz domain are also known as protease nexin 2 (PN2). Normal proteolytic processing of transmembrane APP, which results in the maj ority of soluble PN2, cleaves within the Alzheimer's A beta peptide, p recluding A beta formation. Recent data indicate that soluble PN2 is i nternalized by cells via the low density lipoprotein receptor-related protein (LRP), which binds multiple Ligands including apolipoprotein E (apoE) [23]. However, soluble PN2 cannot contribute to amyloid accumu lation, so we examined whether the unprocessed. transmembrane form of APP751 containing the intact A beta sequence would form complexes with a PN2 ligand. EGF binding protein (EGFBP), and be internalized by LRP . We found that the addition of EGFBP to cells overexpressing APP751 i nduced the internalization of this amyloidogenic form of APP. The 39 k Da LRP receptor associated protein (RAP), an antagonist for LRP, block ed the internalization of APP751/PN2, suggesting a common LRP-mediated internalization pathway for both soluble and transmembrane APP751/PN2 after protease complex formation, previous work has shown that intern alization of transmembrane APP can lead to the formation of amyloidoge nic carboxyl-terminal fragments and increased secretion of the Alzheim er's A beta peptide. Our data suggest the protease ligands for PN2 may play an important role in altering APP processing pathways to favor a myloid formation, and that LRP may be a point at which the apoE and am yloid processing pathways intersect.