RRC ID |
45424
|
著者 |
Takasugi N, Sasaki T, Shinohara M, Iwatsubo T, Tomita T.
|
タイトル |
Synthetic ceramide analogues increase amyloid-β 42 production by modulating γ-secretase activity.
|
ジャーナル |
Biochem Biophys Res Commun
|
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.
|
巻・号 |
457(2)
|
ページ |
194-9
|
公開日 |
2015-2-6
|
DOI |
10.1016/j.bbrc.2014.12.087
|
PII |
S0006-291X(14)02276-1
|
PMID |
25545059
|
MeSH |
Amyloid Precursor Protein Secretases / metabolism*
Amyloid beta-Peptides / biosynthesis*
Animals
Apoptosis / drug effects
Benzyl Alcohols / chemistry
Benzyl Alcohols / pharmacology*
CHO Cells
Ceramides / chemistry*
Cricetinae
Cricetulus
HEK293 Cells
Humans
Mice
Morpholines / chemistry*
Morpholines / pharmacology
Mutation / genetics
Peptide Fragments / biosynthesis*
Up-Regulation / drug effects
|
IF |
2.985
|
引用数 |
10
|
WOS 分野
|
BIOPHYSICS
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
リソース情報 |
ヒト・動物細胞 |
GM95(RCB1026)
MEB4(RCB1027) |