Neuroprotective Actions of Dietary Choline

Abstract

Choline is an essential nutrient for humans. It is a precursor of membrane phospholipids (e.g., phosphatidylcholine (PC)), the neurotransmitter acetylcholine, and via betaine, the methyl group donor S-adenosylmethionine. High choline intake during gestation and early postnatal development in rat and mouse models improves cognitive function in adulthood, prevents age-related memory decline, and protects the brain from the neuropathological changes associated with Alzheimer's disease (AD), and neurological damage associated with epilepsy, fetal alcohol syndrome, and inherited conditions such as Down and Rett syndromes. These effects of choline are correlated with modifications in histone and DNA methylation in brain, and with alterations in the expression of genes that encode proteins important for learning and memory processing, suggesting a possible epigenomic mechanism of action. Dietary choline intake in the adult may also influence cognitive function via an effect on PC containing eicosapentaenoic and docosahexaenoic acids; polyunsaturated species of PC whose levels are reduced in brains from AD patients, and is associated with higher memory performance, and resistance to cognitive decline.

Keywords: Alzheimer’s disease; DNA methylation; autism; brain; choline; epilepsy; memory; nutrition; pregnancy.

Figure 1

Relationship between intake of choline during the second trimester of pregnancy and offspring visual memory assessed by Wide Range Assessment of Memory and Learning, Second Edition (WRAML2). The top quartile choline intake was associated with a child WRAML2 score 1.4 points higher than the bottom quartile (P-trend = 0.003). Figure created from data in [55].

Figure 2

Dose–response relationship between the average daily choline intake and verbal and visual memory performance in non-demented adults. Red lines indicate 95% confidence interval. Figure created from data in [45].

Figure 3

PC-DHA levels depend on nutrition, liver and brain synthesis by PEMT and transport of LPC-DHA across the blood-brain barrier catalyzed by MFSD2A. Plasma PC levels and PC FA molecular species (e.g., PC-DHA) depend on hepatic PC metabolism, the dietary supply of choline and n-3 FA, including DHA, and PC and LPC flux between plasma and tissues (e.g., brain). Hepatic PEMT activity is high and the liver produces large amounts of PC-DHA by methylating PE for the needs of the entire organism. This PC-DHA is secreted by the liver into the circulation as a component of lipoproteins. Brain PEMT activity is relatively low and neuronal and glial PEMT produces PC-DHA to sustain local membranes. PC synthesis by PEMT requires three molecules of SAM that is synthesized from the amino acid, methionine. In addition to PC, PEMT generates SAH that is hydrolyzed to homocysteine. The latter can be converted back to methionine by two pathways: one catalyzed by betaine:homocysteine S-methyltransferase (BHMT) and another catalyzed by vitamin B12-requiring 5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR), in which methyltetrahydrofolate is used as a methyl donor. Betaine is the product of enzymatic oxidation of choline. Thus, dietary choline is used to produce PC directly and to convert homocysteine to methionine and subsequently to SAM. In this fashion the methyl groups derived from dietary choline can be utilized by PEMT to generate PC-DHA. Recent evidence indicates that the main source of brain DHA is LPC-DHA—the circulating deacylated metabolite of PC-DHA. The transport of LPC-DHA from plasma to the brain is catalyzed by MFSD2A. The blue arrows indicate flux and the black arrows represent enzymatic pathways. Protein names are in red. Dietary DHA is primarily stored in PE in tissues and only a small fraction is incorporated directly into PC. Homocysteine can also be converted to cysteine via cystathionine in a transsulfuration pathway that includes two vitamin B6-requiring enzymes, CBS and CTH. Abbreviations: BHMT, betaine:homocysteine S-methyltransferase; CBS, cystathionine-beta-synthase; CTH, cystathionine gamma-lyase; DHA, docosahexaenoic acid; FA, fatty acid; LPC, lysophosphatidylcholine; MFSD2A, major facilitator superfamily domain containing 2a; MTR, 5-methyltetrahydrofolate-homocysteine S-methyltransferase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PEMT, phosphatidylethanolamine N-methyltransferase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine.