RRC ID 45424
Author Takasugi N, Sasaki T, Shinohara M, Iwatsubo T, Tomita T.
Title Synthetic ceramide analogues increase amyloid-β 42 production by modulating γ-secretase activity.
Journal 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.
Volume 457(2)
Pages 194-9
Published 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 2.705
Times Cited 3
Human and Animal Cells