Submitted on August 31, 2004
Revised on January 19, 2005
Accepted on February 1, 2005
Association of active 
-secretase complex with lipid rafts
Yasuomi Urano, Ikuo Hayashi, Noriko Isoo, Patrick C. Reid, Yoshikazu Shibasaki, Noriko Noguchi, Taisuke Tomita, Takeshi Iwatsubo, Takao Hamakubo, and Tatsuhiko Kodama
Department of Molecular Biology and Medicine, University of Tokyo, Tokyo 153-8904
Corresponding Author: hamakubo{at}lsbm.org
Cholesterol has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although the underlying mechanisms are not yet clear, several studies have provided evidence for the involvement of cholesterol-rich lipid rafts in the production of amyloid 
peptide (A), the major component of amyloid deposits in AD. In this regard, the 
-secretase complex is responsible for the final cleavage event in the processing of -amyloid precursor protein (APP), resulting in A generation. The -secretase complex is a multiprotein complex composed of presenilin, nicastrin (NCT), APH-1, and PEN-2. Recent reports have suggested that -secretase activity is predominantly localized in lipid rafts, and presenilin and NCT have been reported to be localized in lipid rafts. In this study various biochemical methods including co-immunoprecipitation, in vitro -secretase assay, and methyl--cyclodextrin (MCD) treatment are employed to demonstrate that all four components of the active endogenous -secretase complex, including APH-1 and PEN-2, are associated with lipid rafts in human neuroblastoma cells (SH-SY5Y). Treatment with statins, 3-hydroxy-3-methylglutaryl-CoA-reductase inhibitors, significantly decreased the association of the -secretase complex with lipid rafts, without affecting the distribution of flotillin-1. This effect was partially abrogated by the addition of geranylgeraniol. These results suggest that both cholesterol and protein isoprenylation influence the active -secretase complex association with lipid rafts.
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