Modulation of amyloid precursor protein processing by synthetic ceramide analogues

被引：17

作者：

Li, Hongyun ^{[1
]}

Kim, Woojin S. ^{[1
,2
]}

Guillemin, Gilles J. ^{[2
]}

Hill, Andrew F. ^{[3
,4
]}

Evin, Genevieve ^{[5
]}

Garner, Brett ^{[1
,6
]}

机构：

[1] Prince Wales Med Res Inst, Randwick, NSW 2031, Australia

[2] Univ New S Wales, Fac Med, Sch Med Sci, Sydney, NSW 2052, Australia

[3] Univ Melbourne, Inst Bio21, Dept Biochem & Mol Biol, Melbourne, Vic 3010, Australia

[4] Mental Hlth Res Inst Victoria, Melbourne, Vic 3010, Australia

[5] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia

[6] Univ Wollongong, Fac Sci, Sch Biol Sci, Wollongong, NSW 2522, Australia

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS | 2010年 / 1801卷 / 08期

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

Glycosphingolipid; Sphingolipids; Amyloid precursor protein; Alzheimer's disease; Neurodegeneration; Amyloid-beta peptide; NERVE GROWTH-FACTOR; ALZHEIMERS-DISEASE; GAMMA-SECRETASE; APOLIPOPROTEIN-E; BETA-PEPTIDE; IN-VIVO; GLUCOSYLCERAMIDE SYNTHASE; CHOLESTEROL EFFLUX; GM1; GANGLIOSIDE; UP-REGULATION;

D O I：

10.1016/j.bbalip.2010.05.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Previous studies suggest that membrane lipids may regulate proteolytic processing of the amyloid precursor protein (APP) to generate amyloid-beta peptide (Abeta). In the present study, we have assessed the capacity for a series of structurally related synthetic ceramide analogues to modulate APP processing in vitro. The compounds tested are established glucosylceramide synthase (GS) inhibitors based on the D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) structure. PDMP and related compounds PPMP and EtDO-P4 inhibited Abeta secretion from Chinese hamster ovary cells expressing human APP (CHO-APP) with approximate IC50 values of 15, 5, and 1 mu M, respectively. A trend for reduced secretion of the APP alpha-secretase product, sAPPalpha, was also observed in PDMP-treated cells but not in PPMP- or ETDO-P4-treated cells, whereas levels of the cellular beta-secretase product APP C-terminal fragment, CTFbeta, were increased by both PDMP and PPMP but unaltered with EtDO-P4 treatment. Our data also revealed that EtDO-P4 inhibits endogenous Abeta production by human neurons. In conclusion, this study provides novel information regarding the regulation of APP processing by synthetic ceramide analogues and reveals that the most potent of these compounds is EtDO-P4. (C) 2010 Elsevier B.V. All rights reserved.

引用

页码：887 / 895

页数：9

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