Modulation of beta-amyloid precursor protein processing by the low densitylipoprotein receptor-related protein (LRP) - Evidence that LRP contributesto the pathogenesis of Alzheimer's disease

beta-Amyloid peptide (A beta), which plays a central role in the pathogenes is of Alzheimer's disease, is derived from the transmembrane beta-amyloid p recursor protein (APP) by proteolytic processing. Although mechanisms assoc iated with A beta generation are not fully understood, it is known that A b eta can be generated within endosomal compartments upon internalization of APP from the cell surface. The low density lipoprotein receptor-related pro tein (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 cur rent study was to test the hypothesis that LRP-mediated internalization of cell surface APP can modulate APP processing and thereby affect A beta gene ration. 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 producti on. These findings demonstrate that LRP contributes to A beta generation an d suggest novel pharmacological approaches to reduce A beta levels based on selective LRP blockade.