Choline production from choline-containing phospholipids: a hypothetical role in Alzheimer's disease and aging

Deficits in certain long-axon cholinergic brain neurons have been demonstrated both in senile dementia of the Alzheimer type (SDAT) and, to a lesser degree, in association with the cognitive and memory impairments sometimes seen with normal aging. Our studies support a hypothesis concerning the selective vulnerability of these neurons. In our superfused brain slice system, acetylcholine (ACh) release was dependent on the concentration of exogenous choline, at rest and during electrical stimulation. Decreases in intracellular levels of ACh and choline accounted for only a small fraction of the quantities of these compounds released into the superfusates, suggesting that some tissue pool of bound choline, such as the phospholipids (PL), might have liberated choline. In choline-free medium, the release and tissue content of ACh were sustained; thus, choline released from the putative endogenous pool can be utilized for ACh synthesis. We hypothesize that the use, by cholinergic neurons, of choline originating from the breakdown of membrane PL, may result in an impoverishment in certain PL. Since only cholinergic neurons use their membrane PL as a reservoir for their neurotransmitter's precursor, this relationship might explain the major deficits in long-axon cholinergic nerve terminals seen in SDAT and other age-related memory disorders.