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Exclusively Targeting β-Secretase to Lipid Rafts by GPI-Anchor Addition Up-Regulates β-Site Processing of the Amyloid Precursor Protein
Joanna M. Cordy, Ishrut Hussain, Colin Dingwall, Nigel M. Hooper and Anthony J. Turner
Proceedings of the National Academy of Sciences of the United States of America
Vol. 100, No. 20 (Sep. 30, 2003), pp. 11735-11740
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3147861
Page Count: 6
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β-Secretase (BACE, Asp-2) is a transmembrane aspartic proteinase responsible for cleaving the amyloid precursor protein (APP) to generate the soluble ectodomain sAPPβ and its C-terminal fragment $CTF\beta.\>CTF\beta$ is subsequently cleaved by β-secretase to produce the neurotoxic/synaptotoxic amyloid-β peptide (Aβ) that accumulates in Alzheimer's disease. Indirect evidence has suggested that amyloidogenic APP processing may preferentially occur in lipid rafts. Here, we show that relatively little wild-type BACE is found in rafts prepared from a human neuroblastoma cell line (SH-SY5Y) by using Triton X-100 as detergent. To investigate further the significance of lipid rafts in APP processing, a glycosylphosphatidylinositol (GPI) anchor has been added to BACE, replacing the transmembrane and C-terminal domains. The GPI anchor targets the enzyme exclusively to lipid raft domains. Expression of GPI-BACE substantially up-regulates the secretion of both sAPPβ and amyloid-β peptide over levels observed from cells overexpressing wild-type BACE. This effect was reversed when the lipid rafts were disrupted by depleting cellular cholesterol levels. These results suggest that processing of APP to the amyloid-β peptide occurs predominantly in lipid rafts and that BACE is the rate-limiting enzyme in this process. The processing of the APP695 isoform by GPI-BACE was up-regulated 20-fold compared with wild-type BACE, whereas only a 2-fold increase in the processing of APP751/770 was seen, implying a differential compartmentation of the APP isoforms. Changes in the local membrane environment during aging may facilitate the cosegregation of APP and BACE leading to increased β-amyloid production.
Proceedings of the National Academy of Sciences of the United States of America © 2003 National Academy of Sciences