title: Sphingosylphosphorylcholine attenuated β-amyloid production by reducing BACE1 expression and catalysis in PC12 cells.
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.
authors.affiliation: Pharmacology Research Center, Korea Research Institute of Chemical Technology, Yuseong, Daejeon 305-343, Korea.
authors.forename: Hyoseok
authors.initials: H
authors.lastname: Yi
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jiyeong
authors.initials: J
authors.lastname: Lee
authors.forename: Chang-Seon
authors.initials: CS
authors.lastname: Myung
authors.forename: Woo-Kyu
authors.initials: WK
authors.lastname: Park
authors.forename: Hee-Jong
authors.initials: HJ
authors.lastname: Lim
authors.forename: Ge Hyeong
authors.initials: GH
authors.lastname: Lee
authors.forename: Jae Yang
authors.initials: JY
authors.lastname: Kong
authors.forename: Heeyeong
authors.initials: H
authors.lastname: Cho
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D015536:Down-Regulation; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D016716:PC12 Cells; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008246:Lysophospholipids; D016328:NF-kappa B; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D013110:Sphingosine