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Sphingosylphosphorylcholine Attenuated β–Amyloid Production by Reducing BACE1 Expression and Catalysis in PC12 Cells

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Abstract

Abnormal accumulation of β-amyloid (Aβ) is the main characteristic of Alzheimer’s disease (AD) brain and Aβ peptides are generated from proteolytic cleavages of amyloid precursor protein (APP) by β-site APP-converting enzyme 1 (BACE1) and presenilin 1 (PS1). Sphingosylphosphorylcholine (SPC), a choline-containing sphingolipid, showed suppressive effect on Aβ production in PC12 cells which stably express Swedish mutant of amyloid precursor protein (APPsw). SPC (>3 μM) significantly lowered the accumulation of Aβ40/42 and the expression of BACE1. However, the transcriptions of other APP processing enzymes like ADAM10 and PS1 were not affected by the SPC addition. Meanwhile, phosphocholine (PC) or other lysophospholipids, such as lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), sphingosyl-1-phosphate (S1P), did not alter BACE1 expression. Down-regulatory effect of SPC on BACE1 expression appeared to be mediated by NF-κB which is known to suppress the trans-activation of BACE1 promoter in PC12 cells. Here, the nuclear tanslocation of NF-κB was enhanced by SPC treatment in immune-fluorescent image analysis and NF-κB reporter assay. Furthermore, the catalytic activities of BACE1 and BACE2 were dose-dependently inhibited by SPC displaying IC50 values of 2.79 μM and 12.05 μM, respectively. Overall, these data suggest that SPC has the potential to ameliorate Aβ pathology in neurons by down-regulating the BACE1-mediated amyloidogenic pathway.

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Acknowledgments

This work was supported by Business of Future-oriented Technology Development program (Grant 2010-0018172), the Global Frontier Project grant (NRF-M1AXA002-2010-0029776) of National Research Foundation funded by the Ministry of Education, Science and Technology of Korea, and a grant from Korea Research Council for Industrial Science and Technology (KK-1103-A0).

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Authors and Affiliations

  1. Pharmacology Research Center, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, 305-343, Korea

    Hyoseok Yi, Seong Jin Lee, Jiyeong Lee, Woo-Kyu Park, Jae Yang Kong & Heeyeong Cho

  2. Department of Pharmacology, College of Pharmacy, Chungnam National University, Yuseong, Daejeon, 305-764, Korea

    Hyoseok Yi & Chang-Seon Myung

  3. Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, 305-343, Korea

    Hee-Jong Lim & Ge Hyeong Lee

  4. College of Pharmacy, Gyeongsang National University, Jinju, Gyeongnam, 660-751, Korea

    Jae Yang Kong

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  1. Hyoseok Yi
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Correspondence to Heeyeong Cho.

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Yi, H., Lee, S.J., Lee, J. et al. Sphingosylphosphorylcholine Attenuated β–Amyloid Production by Reducing BACE1 Expression and Catalysis in PC12 Cells. Neurochem Res 36, 2083–2090 (2011). https://doi.org/10.1007/s11064-011-0532-0

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  • DOI: https://doi.org/10.1007/s11064-011-0532-0

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