Modulation of β-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP) -: Evidence that LRP contributes to the pathogenesis of Alzheimer's disease

beta-Amyloid peptide (A beta), which plays a central role in the pathogenesis of Alzheimer's disease, is derived from the transmembrane beta-amyloid precursor protein (APP) by proteolytic processing. Although mechanisms associated with A beta generation are not fully understood, it is known that A beta can be generated within endosomal compartments upon internalization of APP from the cell surface. The low density lipoprotein receptor-related protein (LRP) was previously shown to mediate the endocytosis of APP isoforms containing the Kunitz proteinase inhibitor domain (Kounnas, M. Z., Moir, R, D,, Rebeck, G. W., Bush, A. I., Argraves, W, S., Tanzi, R. E., Hyman, B, T., and Strickland, D. K. (1995) Cell 82, 331-340; Knauer, M, F., Orlando, R.A., and Glabe, C.G. (1996) Brain Res. 740, 6-14), The objective of the current study was to test the hypothesis that LRP-mediated internalization of cell surface APP can modulate APP processing and thereby affect A beta generation. Here, we show that long term culturing of cells in the presence of the LRP-antagonist RAP leads to increased cell surface levels of APP and a significant reduction in A beta synthesis. Further, restoring LRP function in LRP-deficient cells results in a substantial increase in A beta production. These findings demonstrate that LRP contributes to A beta generation and suggest novel pharmacological approaches to reduce A beta levels based on selective LRP blockade.