DHA Increases PS to Promote Neuronal Survival

Abstract

Docosahexaenoic acid (DHA) is an n-3 polyunsaturated fatty acid, and various neural diseases and deficits in development of the nervous system are associated with deficiency in this lipid. DHA is a precursor for phosphatidylserine (PS) biosynthesis, and addition of DHA increases PS content in brain or in cultured glial or neuronal cells. Akbar et al. show that supplementation of Neuro 2A cells with varying ratios of DHA and DPA (docosapentaenoic acid, a saturated lipid) showed that DHA promoted the greatest increase in PS concentration and was most effective at preventing apoptosis in cells deprived of serum. Pharmacological inhibition of phosphoinositide 3-kinase (PI3K) blocked the cell survival effect of DHA, and enrichment of cells with DHA partially rescued the phosphorylation and activity of the protein kinase Akt (a downstream effector in the PI3K pathway) in the absence of serum. Neuro 2A cells enriched with DHA or DPA (both of which increase PS concentration) showed faster recruitment of Akt to the membrane and faster phosphorylation of Akt upon stimulation of the cells with insulin-like growth factor (IGF). DHA resulted in the fastest redistribution, and this faster redistribution was not seen if the cells were grown in serine-depleted medium, suggesting that the increase in PS was responsible for this effect. In support of Akt directly interacting with PS, mutant forms of Akt (R67A or R69A) that may not bind acidic phospholipids translocated to a lesser extent to the membrane upon cell stimulation, and DHA or DPA did not alter the translocation of these mutants to the membrane. Hippocampal neurons from embryonic rats isolated from a rat fed either a normal or an n-3 fatty acid-deficient diet showed that the cells from the deficient rats had 15% less PS and that the cells were more susceptible to cell death following trophic withdrawal than were the DHA-replete cells. Thus, the abundance of PS in the inner plasma membrane leaflet appears to contribute to the recruitment of Akt in the cell survival pathway in neurons, and this may explain the neuronal deficits associated with n-3 fatty acid deficiency. M. Akbar, F. Calderon, Z. Wen, H. Y. Kim, Docosahexaenoic acid: A positive modulator of Akt signaling in neuronal survival. Proc. Natl. Acad. Sci. U.S.A. 102 , 10858-10863 (2005). [Abstract] [Full Text]