【摘 要】
：
Inhibition of glycosphingolipid (GSL) synthesis reduces amyloid-beta (Aβ) production in vitro.Previous studies indicate that glucosylceramide synthase (GCS) inhibitors modulate phosphorylation of extr
【机 构】
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Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollon
【出 处】
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中国神经科学学会第九届全国学术会议暨第五届会员代表大会
论文部分内容阅读
Inhibition of glycosphingolipid (GSL) synthesis reduces amyloid-beta (Aβ) production in vitro.Previous studies indicate that glucosylceramide synthase (GCS) inhibitors modulate phosphorylation of extracellular signal-regulated kinase 1/2 (ERK) and that the ERK pathway may regulate some aspects of Aβ production.It is not clear if there is a causative relationship linking GSL synthesis inhibition, ERK phosphorylation, and Aβ production.Here we treated CHO cells that constitutively express human wild type amyloid-beta precursor protein (CHO-APP), and process this to produce Aβ, with GSL-modulating agents to explore this relationship.We found that three related ceramide analogue GSL inhibitors, based on the D-threo-l-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) structure, reduced Aβ production by CHO-APP cells and in all cases this was correlated with suppression of pERK formation.Importantly, the L-threo enantiomers of these compounds (that are inferior GSL synthesis inhibitors compared to the D-threo enantiomers) also reduced ERK phosphorylation to a similar extent without altering Aβ production.Inhibition of ERK activation using either 2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) or 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (U0126) had no impact on Aβ production and knockdown of endogenous GCS using siRNA reduced cellular GSL levels without suppressing Aβ production or pERK formation.Our data suggest that the alteration in pERK levels following treatment with these ceramide analogues is not the principal mechanism involved in the inhibition of Aβ generation, and that the ERK signaling pathway does not play a crucial role in processing APP through the amyloidogenic pathway.
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