gamma-Secretase cleaves amyloid beta-precursor protein (APP) to generate amyloid-beta peptide (A beta), which is a causative molecule of Alzheimer disease (AD). The C-terminal length of A beta, which is determined by gamma-secretase activity, determines the aggregation and deposition profiles of A beta, thereby affecting the onset of AD. In this study, we found that the synthetic ceramide analogues DL-threo-1-phenyl-2-decanoylami-no-3-morpholino-1-propanol (PDMP) and (1S,2R-D-erythro-2-N-myristoylamino)-1-phenyl-1-propanol (DMAPP) modulated gamma-secretase-mediated cleavage to increase A beta 42 production. Unexpectedly, PDMP and DMAPP upregulated A beta 42 production independent of alteration of ceramide metabolism. Our results propose that synthetic ceramide analogues function as novel gamma-secretase modulators that increase A beta 42, and this finding might lead to the understanding of the effect of the lipid environment on gamma-secretase activity. (C) 2014 Elsevier Inc. All rights reserved.