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Journal of Lipid Research, Vol. 45, 2368-2376, December 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

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

Yanzhu Liu^*, Lin Yang^*, Karin Conde-Knape^*, Dirk Beher, Mark S. Shearman and Neil S. Shachter^1,*

^* Department of Medicine, Columbia University, New York, NY
Department of Molecular and Cellular Neuroscience, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, United Kingdom

¹ To whom correspondence should be addressed. e-mail: nss5{at}columbia.edu

Presenilin-1 (PS1) is an important determinant of the -secretase activity necessary for the generation of ß-amyloid (Aß), 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 -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 Aß. This effect was independent of any secondary increase in cellular cholesterol. Cells cultured in 0.4 mM OA also exhibited significantly increased -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 -secretase activity.

Abbreviations: Aß, ß-amyloid; AD, Alzheimer's disease; apoE, apolipoprotein E; APP, amyloid precursor protein; CD, cyclodextrin; CMV, cytomegalovirus; ECL, enhanced chemiluminescence; GST, glutathione S-transferase; LA, linoleic acid; MTT, methylthiazoltetrazolium; OA, oleic acid; PS1, presenilin-1; PS1-CTF, C-terminal fragment of cleaved PS1; PS1-NTF, N-terminal fragment of cleaved PS1; SREBP, sterol regulatory element binding protein; TG, triglyceride

Supplementary key words oleic acid • linoleic acid • emulsion • triglycerides • cholesterol • CHO cells • Alzheimer's disease • apolipoprotein E • presenilin • amyloid ß-protein precursor

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