Modulation of amyloid precursor protein processing by synthetic ceramide analogues.
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 IC(50) values of 15, 5, and 1 microM, 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.
Li
Hongyun
H
Prince of Wales Medical Research Institute, Randwick, NSW 2031, Australia.
Kim
Woojin S
WS
Guillemin
Gilles J
GJ
Hill
Andrew F
AF
Evin
Genevieve
G
Garner
Brett
B
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002518:Ceramides / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D003603:Cytotoxins / Q000494:pharmacology; D005333:Fetus / Q000378:metabolism; D006801:Humans; D008614:Meperidine / Q000031:analogs & derivatives / Q000494:pharmacology; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology
C404730:3',4'-ethylenedioxyphenyl-2-palmitoylamino-3-pyrrolidino-1-propanol; D016564:Amyloid beta-Protein Precursor; D002518:Ceramides; D003603:Cytotoxins; D009025:Morpholines; D011412:Propanolamines; D011759:Pyrrolidines; C026733:4-propionyloxy-4-phenyl-N-methylpiperidine; C033110:RV 538; D008614:Meperidine