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Dissociation of ERK signalling inhibition from the anti-amyloidogenic action of synthetic ceramide analogues

Journal Article


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Abstract


  • Inhibition of GSL (glycosphingolipid) synthesis reduces Aβ (amyloid β-peptide) production

    in vitro. Previous studies indicate that GCS (glucosylceramide synthase) inhibitors modulate

    phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) and that the ERK pathway

    may regulate some aspects of Aβ production. It is not clear whether there is a causative relationship

    linking GSL synthesis inhibition, ERK phosphorylation and Aβ production. In the present study,

    we treated CHO cells (Chinese-hamster ovary cells) and SH-SY5Y neuroblastoma cells, that

    both constitutively express human wild-type APP (amyloid precursor protein) 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 PDMP (D-threo-1-phenyl-2-decanoylamino-

    3-morpholino-1-propanol) structure, reduced cellular Aβ production and in all cases this was

    correlated with inhibition of pERK (phosphorylated ERK) formation. Importantly, the L-threo

    enantiomers of these compounds (that are inferior GSL synthesis inhibitors compared with the

    D-threo-enantiomers) also reduced ERK phosphorylation to a similar extent without altering Aβ

    production. Inhibition of ERK activation using either PD98059 [2-(2-amino-3-methoxyphenyl)-4H-

    1-benzopyran-4-one] or U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene)

    had no impact on Aβ production, and knockdown of endogenous GCS using small interfering

    RNA 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 signalling

    pathway does not play a crucial role in processing APP through the amyloidogenic pathway.

Authors


  •   Li, Henry (external author)
  •   Dr Genevieve Evin, Genevieve (external author)
  •   Hill, Andrew F. (external author)
  •   HUNG, Ya Hui (external author)
  •   BUSH, Ashley I. (external author)
  •   Garner, Brett

Publication Date


  • 2012

Citation


  • Li, H., Evin, G., Hill, A. F., Hung, Y., Bush, A. I. & Garner, B. (2012). Dissociation of ERK signalling inhibition from the anti-amyloidogenic action of synthetic ceramide analogues. Clinical Science, 122 (9), 409-419.

Scopus Eid


  • 2-s2.0-84857765070

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=8080&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/4737

Has Global Citation Frequency


Number Of Pages


  • 10

Start Page


  • 409

End Page


  • 419

Volume


  • 122

Issue


  • 9

Place Of Publication


  • United Kingdom

Abstract


  • Inhibition of GSL (glycosphingolipid) synthesis reduces Aβ (amyloid β-peptide) production

    in vitro. Previous studies indicate that GCS (glucosylceramide synthase) inhibitors modulate

    phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) and that the ERK pathway

    may regulate some aspects of Aβ production. It is not clear whether there is a causative relationship

    linking GSL synthesis inhibition, ERK phosphorylation and Aβ production. In the present study,

    we treated CHO cells (Chinese-hamster ovary cells) and SH-SY5Y neuroblastoma cells, that

    both constitutively express human wild-type APP (amyloid precursor protein) 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 PDMP (D-threo-1-phenyl-2-decanoylamino-

    3-morpholino-1-propanol) structure, reduced cellular Aβ production and in all cases this was

    correlated with inhibition of pERK (phosphorylated ERK) formation. Importantly, the L-threo

    enantiomers of these compounds (that are inferior GSL synthesis inhibitors compared with the

    D-threo-enantiomers) also reduced ERK phosphorylation to a similar extent without altering Aβ

    production. Inhibition of ERK activation using either PD98059 [2-(2-amino-3-methoxyphenyl)-4H-

    1-benzopyran-4-one] or U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene)

    had no impact on Aβ production, and knockdown of endogenous GCS using small interfering

    RNA 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 signalling

    pathway does not play a crucial role in processing APP through the amyloidogenic pathway.

Authors


  •   Li, Henry (external author)
  •   Dr Genevieve Evin, Genevieve (external author)
  •   Hill, Andrew F. (external author)
  •   HUNG, Ya Hui (external author)
  •   BUSH, Ashley I. (external author)
  •   Garner, Brett

Publication Date


  • 2012

Citation


  • Li, H., Evin, G., Hill, A. F., Hung, Y., Bush, A. I. & Garner, B. (2012). Dissociation of ERK signalling inhibition from the anti-amyloidogenic action of synthetic ceramide analogues. Clinical Science, 122 (9), 409-419.

Scopus Eid


  • 2-s2.0-84857765070

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=8080&context=scipapers

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/4737

Has Global Citation Frequency


Number Of Pages


  • 10

Start Page


  • 409

End Page


  • 419

Volume


  • 122

Issue


  • 9

Place Of Publication


  • United Kingdom