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- W2154168208 abstract "BACE1 is a major beta-secretase for production of amyloid-beta peptide (Abeta). BACE1 resides in the lipid raft, a membrane microdomain enriched in cholesterol and sphingolipids, and a significant role of lipids and microdomain is implicated in the regulation of the beta-cleavage. In this study, we focused on a biologically active lipid metabolite, sphingosine-1-phosphate (S1P) in the regulation of BACE1 activity. We analyzed the impact of cellular S1P levels on BACE1 activity in neuronal cells as well as animal model using small compounds and RNAi knockdown. Moreover, we analyzed the brains of patients with sporadic AD. We show that modulation of sphingosine kinases and S1P degrading enzymes, which are responsible enzymes for S1P production and catabolism, respectively, altered the Abeta generation by regulating the beta-cleavage. We found that BACE1 protein was specifically pulled down by S1P-coated beads, suggesting that modulatory action of S1P is mediated by direct interaction of S1P on BACE1 protein. Moreover, small compounds that inhibit S1P production significantly reduced the brain Abeta levels in AD model mouse. Finally, we found that the relative activity of sphingosine kinase 2 was increased in the brains of patients with sporadic AD. S1P metabolism in brain might be a novel molecular target for AD therapeutics." @default.
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- W2154168208 date "2011-07-01" @default.
- W2154168208 modified "2023-10-02" @default.
- W2154168208 title "P2-315: BACE1 activity is modulated by cell-associated sphingosine-1-phosphate" @default.
- W2154168208 doi "https://doi.org/10.1016/j.jalz.2011.05.1193" @default.
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