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
N1 - Funding Information:
The authors are grateful to Takeda Pharmaceutical Company for the Aβ ELISA detection system, and our current and previous laboratory members for helpful discussions and technical assistance. We also thank the RIKEN cell bank for the MEB4 and GM95 cell lines. This work was supported in part by Grants-in-Aid for Young Scientists (S) (to T.T.) and (B) (to N.T.) from the Japan Society for the Promotion of Science, Japan , and by a Grant-in-Aid for Scientific Research on Innovative Areas (Brain Environment) from the Ministry of Education, Culture, Sports, Science & Technology in Japan (to T.T.).
Publisher Copyright:
© 2014 Elsevier Inc. All rights reserved.
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
SN - 0006-291X
VL - 457
SP - 194
EP - 199
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -