Synthetic ceramide analogues increase amyloid-β 42 production by modulating γ-secretase activity

Nobumasa Takasugi, Tomoki Sasaki, Mitsuru Shinohara, Takeshi Iwatsubo, Taisuke Tomita

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

γ-Secretase cleaves amyloid β-precursor protein (APP) to generate amyloid-β peptide (Aβ), which is a causative molecule of Alzheimer disease (AD). The C-terminal length of Aβ, which is determined by γ-secretase activity, determines the aggregation and deposition profiles of Aβ, thereby affecting the onset of AD. In this study, we found that the synthetic ceramide analogues DL-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and (1S,2R-D-erythro-2-N-myristoylamino)-1-phenyl-1-propanol (DMAPP) modulated γ-secretase-mediated cleavage to increase Aβ42 production. Unexpectedly, PDMP and DMAPP upregulated Aβ42 production independent of alteration of ceramide metabolism. Our results propose that synthetic ceramide analogues function as novel γ-secretase modulators that increase Aβ42, and this finding might lead to the understanding of the effect of the lipid environment on γ-secretase activity.

Original languageEnglish
Pages (from-to)194-199
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume457
Issue number2
DOIs
Publication statusPublished - Feb 6 2015
Externally publishedYes

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Keywords

  • Alzheimer disease
  • Amyloid
  • Ceramide
  • Secretase

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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