Bradley T. Hyman

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

β-Amyloid peptide (Aβ), which plays a central role in the pathogenesis of Alzheimers disease, is derived from the transmembrane β-amyloid precursor protein (APP) by proteolytic processing. Although mechanisms associated with Aβ generation are not fully understood, it is known that Aβ 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 Aβ 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 Aβ synthesis. Further, restoring LRP function in LRP-deficient cells results in a substantial increase in Aβ production. These findings demonstrate that LRP contributes to Aβ generation and suggest novel pharmacological approaches to reduce Aβ levels based on selective LRP blockade.