Reference - Detail
|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.|
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.
|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|
|WOS Category||BIOPHYSICS BIOCHEMISTRY & MOLECULAR BIOLOGY|
|Human and Animal Cells|