Phosphatidylcholine as a precursor of choline for acetylcholine synthesis

It has been hypothesized that the selective vulnerability of certain brain cholinergic neurons in Alzheimer's disease may reflect the unique way that choline is utilized by these neurons, i.e. not only as a component of major membrane phospholipids, e.g. phosphatidylcholine (PC), but also as a precursor of their neurotransmitter, acetylcholine (ACh). A prolonged utilization of choline liberated from PC, for ACh production, without adequate resynthesis of this lipid, might result in a net loss of the phosphatide followed by an impairment of membrane function and loss of cellular viability. Studies described in this paper, performed on electrically stimulated striatal slices and on cholinergic cell lines, test this hypothesis. 1) Electrically-stimulated striatal slices continue to release ACh, and sustain their free choline and ACh levels, even when perfused with a choline-free medium. Striatal levels of PC decline under these circumstances, and this decline can be blocked by adding tetrodotoxin (which blocks neuronal depolarization) or choline to the medium. The other major membrane phospholipids, phosphatidylserine and phosphatidylethanolamine, also decline proportionately to PC when slices are stimulated in the absence of choline. 2) In a population of purely cholinergic cells (human neuroblastoma, LA-N-2), ACh can be synthesized from choline derived from degradation of endogenous PC formed de novo by methylation of phosphatidylethanolamine. 3) PC content of cells in culture (neuroblastoma X glioma hybrid, NG 108-15) can be altered by adding various amounts of choline to the growth media. The proportion of PC in the cells apparently affects cellular survival and rate of growth. Taken together these data demonstrate that cholinergic neurons utilize the choline stored in PC to synthesize ACh; that this process may lead to a depletion in membrane phospholipids (when choline supply is inadequate); and that the resulting changes in neuronal membrane composition might adversely affect cellular viability.