Association of active γ-secretase complex with lipid rafts. J Lipid Res

Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
The Journal of Lipid Research (Impact Factor: 4.42). 06/2005; 46(5):904-12. DOI: 10.1194/jlr.M400333-JLR200
Source: PubMed


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 beta peptide (Abeta), the major component of amyloid deposits in AD. In this regard, the gamma-secretase complex is responsible for the final cleavage event in the processing of beta-amyloid precursor protein (betaAPP), resulting in Abeta generation. The gamma-secretase complex is a multiprotein complex composed of presenilin, nicastrin (NCT), APH-1, and PEN-2. Recent reports have suggested that gamma-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 gamma-secretase assay, and methyl-beta-cyclodextrin (MbetaCD) treatment, are employed to demonstrate that all four components of the active endogenous gamma-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 gamma-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 gamma-secretase complex association with lipid rafts.

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    • "24S-OHC has been shown to more preferentially than 27-OHC favor the processing of APP to the non-amyloidogenic pathway [65]. The processing of APP into A by -secretase and -secretase is thought to occur in the trans-Golgi network and endosomes [66] [67] [68]. APP budding via coat protein complex II (COPII) vesicles from the ER was reduced by 70% in 24S-OHC-treated cells [69]. "
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    ABSTRACT: 24(S)-hydroxycholesterol (24S-OHC), which is enzymatically produced in the brain, has been known to play an important role in maintaining cholesterol homeostasis in the brain and has been proposed as a possible biomarker of neurodegenerative disease. Recent studies have revealed diverse functions of 24S-OHC and gained increased attention. For example, 24S-OHC at sub-lethal concentrations has been found to induce adaptive response via activation of the liver X receptor signaling pathway, thereby protecting neuronal cells against subsequent oxidative stress. It has also been found that physiological concentrations of 24S-OHC suppress amyloid-β production via down-regulation of amyloid precursor protein trafficking in neuronal cells. On the other hand, high concentrations of 24S-OHC have been found to induce a type of non-apoptotic programmed cell death in neuronal cells expressing little caspase-8. Since neuronal cell death induced by 24S-OHC has been found to proceed by a unique mechanism which is different from but in some ways similar to necroptosis-necroptosis being a type of programmed necrosis induced by tumor necrosis factor α-neuronal cell death induced by 24S-OHC has been called "necroptosis-like" cell death. 24S-OHC-induced cell death is dependent on formation of 24S-OHC esters but not on oxidative stress. This review article discusses newly reported aspects of 24S-OHC in neuronal cell death and sheds light on the possible importance of controlling 24S-OHC levels in the brain for preventing neurodegenerative disease. Copyright © 2015. Published by Elsevier Inc.
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    • "and others showed that c-secretase resides in lipid rafts [11] [12], and this lipid raft localization of c-secretase affects the metabolism of Ab in vitro [13] and in vivo [14]. In particular, the components of sphingolipids , including ceramides that compose lipid rafts, were found to modulate c-secretase activity in in vitro assays [13] [15], suggesting that c-secretase activity is modulated by the lipid microenviron- ment. "
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    ABSTRACT: γ-Secretase cleaves amyloid β-precursor protein (APP) to generate amyloid-β peptide (Aβ), which is a causative molecule of Alzheimer disease (AD). The C-terminal length of Aβ, which is determined by γ-secretase activity, determines the aggregation and deposition profiles of Aβ, thereby affecting the onset of AD. In this study, we found that the synthetic ceramide analogues DL-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and (1S,2R-D-erythro-2-N-myristoylamino)-1-phenyl-1-propanol (DMAPP) modulated γ-secretase-mediated cleavage to increase Aβ42 production. Unexpectedly, PDMP and DMAPP upregulated Aβ42 production independent of alteration of ceramide metabolism. Our results propose that synthetic ceramide analogues function as novel γ-secretase modulators that increase Aβ42, and this finding might lead to the understanding of the effect of the lipid environment on γ-secretase activity. Copyright © 2014. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 12/2014; 457(2). DOI:10.1016/j.bbrc.2014.12.087 · 2.30 Impact Factor
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    • "All Trk receptors associate with the pan-neurotrophin receptor p75NTR (Bibel et al., 1999). A critical step in the induction of apoptosis by TrkA is the release of the intracellular death domain of p75NTR by the protease -secretase (Nikoletopoulou et al., 2010), which is localized in lipid rafts (Urano et al., 2005). Our membrane fractionation studies indicate that while TrkA and TrkC associate with p75NTR in lipid rafts, TrkB associated with p75NTR is excluded from this membrane domain (unpublished data). "
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