The secreted isoforms of the amyloid precursor protein (APP) that contain the Kunitz domain are also known as protease nexin 2 (PN2). Normal proteolytic processing of transmembrane APP, which results in the majority of soluble PN2, cleaves within the Alzheimer's A beta peptide, precluding A beta formation. Recent data indicate that soluble PN2 is internalized 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 accumulation, 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 induced the internalization of this amyloidogenic form of APP. The 39 kDa LRP receptor associated protein (RAP), an antagonist for LRP, blocked 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 internalization of transmembrane APP can lead to the formation of amyloidogenic carboxyl-terminal fragments and increased secretion of the Alzheimer's A beta peptide. Our data suggest the protease ligands for PN2 may play an important role in altering APP processing pathways to favor amyloid formation, and that LRP may be a point at which the apoE and amyloid processing pathways intersect.