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Journal of Lipid Research, Vol. 46, 904-912, May 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

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^1,*, and Tatsuhiko Kodama

^* Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan

¹ To whom correspondence should be addressed. e-mail: 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 ß peptide (Aß), 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 ß-amyloid precursor protein (ßAPP), resulting in Aß 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 coimmunoprecipitation, in vitro -secretase assay, and methyl-ß-cyclodextrin (MßCD) 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.

Abbreviations: Aß, amyloid ß peptide; AD, Alzheimer's disease; ßAPP, ß-amyloid precursor protein; CHAPSO, 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate; CTF, C-terminal fragment; DRM, detergent-resistant membrane; LPDS, lipoprotein-deficient serum; MßCD, methyl-ß-cyclodextrin; NCT, nicastrin; NTF, N-terminal fragment

Supplementary key words Alzheimer's disease • statin • cholesterol • isoprenylation • presenilin • nicastrin • APH-1 • PEN-2

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