Neuroprotective actions of perinatal choline nutrition

Abstract

Choline is an essential nutrient for humans. Studies in rats and mice have shown that high choline intake during gestation or the perinatal period improves cognitive function in adulthood, prevents memory decline of old age, and protects the brain from damage and cognitive and neurological deterioration associated with epilepsy and hereditary conditions such as Down's and Rett syndromes. These behavioral changes are accompanied by modified patterns of expression of hundreds of cortical and hippocampal genes including those encoding proteins central for learning and memory processing. The effects of choline correlate with cerebral cortical changes in DNA and histone methylation, thus suggesting an epigenomic mechanism of action of perinatal choline.

Figure 1. Americans consume less choline than recommended

Average daily choline intake reported in three independent studies. The red bars indicate the intake within the bounding values of the quintiles (A, B) or quartiles (C). The yellow strip indicates the Adequate Intake for adults. Data from refs. – (panels A-C, respectively).

Figure 2. Performance of P18–19 prenatally choline supplemented and control rats during cued- and spatial training in the Morris water maze

A) Cued training, rats learn the marked platform location (top panel): both choline-supplemented and control rats at P18–19 learned the location of the platform (lower panel). B) Spatial training, rats use relational cues to learn how to navigate to the platform (top panel): only choline supplemented rats showed improved performance across trials (lower panel). Data from ref. .

Figure 3. Choline and methyl group metabolism

Choline is used as a precursor of phosphatidylcholine, acetylcholine [in a reaction catalyzed by choline acetyltransferase (CHAT)], or betaine [in a reaction catalyzed by choline dehydrogenase (CHDH)]. The methyl groups of betaine are used by betaine:homocysteine S-methyltransferase (BHMT) to regenerate methionine from homocysteine. In an alternative pathway, catalyzed by vit. B12-requiring 5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR), methyltetrahydrofolate (5-CH₃THF) is used as a methyl donor. Methionine is used as a precursor of S-adenosylmethionine (SAM) in a reaction catalyzed by methionine adenosyltransferase(s) (MAT1A). SAM is used by multiple methylating enzymes including DNA and histone methyltransferases that use SAM as a donor of methyl groups to methylate DNA at the 5-position of cytosine residues within the CpG sequences and histones at specific lysine and arginine residues. The DNA methylation state and pattern exerts a modulatory influence on expression of multiple genes (e.g. Igf2). The second product of this, and all other SAM-requiring methylation reactions, S-adenosylhomocysteine (SAH) is hydrolyzed to free homocysteine by SAH hydrolase (AHCY). The metabolic pathway linking choline to DNA and histone methylations is indicated by thick arrows.