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Modulation of amyloid precursor protein processing by synthetic ceramide analogues

Journal Article


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Abstract


  • 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.

Authors


  •   Li, Henry (external author)
  •   Kim, Woojin S. (external author)
  •   Guillemin, Gilles (external author)
  •   Hill, Andrew F. (external author)
  •   Dr Genevieve Evin, Genevieve (external author)
  •   Garner, Brett

Publication Date


  • 2010

Citation


  • Li, H., Kim, W., Guillemin, G., Hill, A. F., Evin, G. & Garner, B. (2010). Modulation of amyloid precursor protein processing by synthetic ceramide analogues. BBA - Molecular and Cell Biology of Lipids, 1801 (8), 887-895.

Scopus Eid


  • 2-s2.0-77953275293

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2114&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/1048

Has Global Citation Frequency


Number Of Pages


  • 8

Start Page


  • 887

End Page


  • 895

Volume


  • 1801

Issue


  • 8

Abstract


  • 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.

Authors


  •   Li, Henry (external author)
  •   Kim, Woojin S. (external author)
  •   Guillemin, Gilles (external author)
  •   Hill, Andrew F. (external author)
  •   Dr Genevieve Evin, Genevieve (external author)
  •   Garner, Brett

Publication Date


  • 2010

Citation


  • Li, H., Kim, W., Guillemin, G., Hill, A. F., Evin, G. & Garner, B. (2010). Modulation of amyloid precursor protein processing by synthetic ceramide analogues. BBA - Molecular and Cell Biology of Lipids, 1801 (8), 887-895.

Scopus Eid


  • 2-s2.0-77953275293

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=2114&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/1048

Has Global Citation Frequency


Number Of Pages


  • 8

Start Page


  • 887

End Page


  • 895

Volume


  • 1801

Issue


  • 8