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

Fingerprint

Amyloid Precursor Protein Secretases
Ceramides
Amyloid
Alzheimer Disease
1-Propanol
Morpholinos
Metabolism
Modulators
Agglomeration
Lipids
Molecules

Keywords

  • Alzheimer disease
  • Amyloid
  • Ceramide
  • Secretase

ASJC Scopus subject areas

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

Cite this

Synthetic ceramide analogues increase amyloid-β 42 production by modulating γ-secretase activity. / Takasugi, Nobumasa; Sasaki, Tomoki; Shinohara, Mitsuru; Iwatsubo, Takeshi; Tomita, Taisuke.

In: Biochemical and Biophysical Research Communications, Vol. 457, No. 2, 06.02.2015, p. 194-199.

Research output: Contribution to journalArticle

Takasugi, Nobumasa ; Sasaki, Tomoki ; Shinohara, Mitsuru ; Iwatsubo, Takeshi ; Tomita, Taisuke. / Synthetic ceramide analogues increase amyloid-β 42 production by modulating γ-secretase activity. In: Biochemical and Biophysical Research Communications. 2015 ; Vol. 457, No. 2. pp. 194-199.
@article{4d940c4c44794274ac9c4a0350b773a5,
title = "Synthetic ceramide analogues increase amyloid-β 42 production by modulating γ-secretase activity",
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.",
keywords = "Alzheimer disease, Amyloid, Ceramide, Secretase",
author = "Nobumasa Takasugi and Tomoki Sasaki and Mitsuru Shinohara and Takeshi Iwatsubo and Taisuke Tomita",
year = "2015",
month = "2",
day = "6",
doi = "10.1016/j.bbrc.2014.12.087",
language = "English",
volume = "457",
pages = "194--199",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Synthetic ceramide analogues increase amyloid-β 42 production by modulating γ-secretase activity

AU - Takasugi, Nobumasa

AU - Sasaki, Tomoki

AU - Shinohara, Mitsuru

AU - Iwatsubo, Takeshi

AU - Tomita, Taisuke

PY - 2015/2/6

Y1 - 2015/2/6

N2 - 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.

AB - 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.

KW - Alzheimer disease

KW - Amyloid

KW - Ceramide

KW - Secretase

UR - http://www.scopus.com/inward/record.url?scp=84921779973&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921779973&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2014.12.087

DO - 10.1016/j.bbrc.2014.12.087

M3 - Article

C2 - 25545059

AN - SCOPUS:84921779973

VL - 457

SP - 194

EP - 199

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 2

ER -