Fatty acids increase presenilin-1 levels and [gamma]-secretase activity in PSwt-1 cells

Presenilin-1 (PS1) is an important determinant of the gamma-secretase activity necessary for the generation of beta-amyloid (Abeta), likely the central pathogenic molecule in Alzheimer's disease. Most presenilin is rapidly degraded, and determinants of the level of the active cleaved form are unknown. We examined the influence of fatty acids on PS1 levels and gamma-secretase activity using stably transfected CHO cells that express human PS1 and the human amyloid precursor protein. Cells cultured with 0.4 mM oleic acid (OA), with 0.1 mM linoleic acid, or with a triglyceride emulsion expressed increased PS1 and Abeta. This effect was independent of any secondary increase in cellular cholesterol. Cells cultured in 0.4 mM OA also exhibited significantly increased gamma-secretase activity. PS1 mRNA levels were unchanged, and pulse-chase experiments indicated that OA slowed presenilin holoprotein degradation. Nontransfected human neuroblastoma cells also showed increased presenilin when cultured in 0.4 mM OA. Lipids may be important biological determinants of PS1 level and gamma-secretase activity.