Neuroprotective Actions of Dietary Choline

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

A Narrative Review on Maternal Choline Intake and Liver Function of the Fetus and the Infant; Implications for Research, Policy, and Practice

Dietary choline is needed to maintain normal health, including normal liver function in adults. Fatty liver induced by a choline-deficient diet has been consistently observed in human and animal studies. The effect of insufficient choline intake on hepatic fat accumulation is specific and reversible when choline is added to the diet. Choline requirements are higher in women during pregnancy and lactation than in young non-pregnant women. We reviewed the evidence on whether choline derived from the maternal diet is necessary for maintaining normal liver function in the fetus and breastfed infants. Studies have shown that choline from the maternal diet is actively transferred to the placenta, fetal liver, and human milk. This maternal-to-child gradient can cause depletion of maternal choline stores and increase the susceptibility of the mother to fatty liver. Removing choline from the diet of pregnant rats causes fatty liver both in the mother and the fetus. The severity of fatty liver in the offspring was found to correspond to the severity of fatty liver in the respective mothers and to the duration of feeding the choline-deficient diet to the mother. The contribution of maternal choline intake in normal liver function of the offspring can be explained by the role of phosphatidylcholine in lipid transport and as a component of cell membranes and the function of choline as a methyl donor that enables synthesis of phosphatidylcholine in the liver. Additional evidence is needed on the effect of choline intake during pregnancy and lactation on health outcomes in the fetus and infant. Most pregnant and lactating women are currently not achieving the adequate intake level of choline through the diet. Therefore, public health policies are needed to ensure sufficient choline intake through adding choline to maternal multivitamin supplements

IGF2 infusion increases BMP9 expression and modulates the levels of its receptor, ALK1.

<p>Septal lysates from WT/CHGFP and APP.PS1/CHGFP mice were analyzed by RT-PCR to determine <i>Bmp9</i> mRNA levels (A,B). Hippocampal lysates were used to determine BMP9 and ALK1 protein levels by immunoblot (C,D,E). Data were analyzed by two-way ANOVA followed by a post-hoc Fisher’s LSD test. IGF2 infusion increased the expression of BMP9 mRNA levels within the septum [F(1, 20) = 12.885, p = 0.002]. Significant differences in BMP9 mRNA between groups are indicated by * (p = 0.003) (B, see bracket). BMP9 protein levels in the hippocampus were also significantly increased by the infusion of IGF2 [F(1, 20) = 21.770, p = 0.0002]. Significant differences in BMP9 protein level between groups are indicated by * (p = 0.001), # (p = 0.025), and † (p = 0.046) (D, see brackets). IGF2 treatment decreased the expression of ALK1 protein [F(1, 20) = 5.724, p = 0.026]. Significant differences in ALK1 protein level between groups are indicated by * (p = 0.031) (E, see bracket).</p

IGF2 infusion alters the level of NGF, NT3, BDNF, FGF2 and IGF1 in WT/CHGFP and APP.PS1/CHGFP mice.

<p>Hippocampal lysates were used to assay NGF (A), NT3 (B), BDNF (C), FGF2 (D) and IGF1 levels (E) by ELISA. IGF2 infusion increased the levels of all of these growth factors as determined by two-way ANOVA [NGF: F(1, 20) = 4.422, p = 0.047; NT3: F(1, 20) = 7.551, p = 0.012; BDNF: F(1, 20) = 6.373, p = 0.020; FGF2: F(1, 20) = 8.348, p = 0.009; and IGF1: F(1, 20) = 6.115, p = 0.022]. In addition, significant differences between groups are indicated by # (p = 0.047) (D, see bracket).</p

IGF2 infusion reduces the number of Aβ40 and Aβ42 plaques in the hippocampus.

<p>Immunohistochemistry for Aβ40 (left) and Aβ42 (right) was performed on anterior, intermediate and posterior hippocampal sections from 6-month old APP.PS1/CHGFP mice. Representative images from each treatment group are shown. The number of Aβ40 (left) and Aβ42 (right) plaques within each of the hippocampal sections was counted and means per group are presented for each region. IGF2 treatment significantly reduced the number of hippocampal plaques as determined by one-way ANOVA with repeated measures [A, F(1,10) = 6.987, p = 0.027; B, F(1,10) = 6.483, p = 0.029]. Scale bar represents 1 mm.</p

IGF2 infusion increases doublecortin (DCX) expression in the dentate gyrus.

<p>Hippocampal sections from WT/CHGFP and APP.PS1/CHGFP mice were stained with anti-DCX antibody and imaged using a confocal microscope (A). Hippocampal lysates were used to determine DCX protein levels by immunoblot (B). Data were analyzed by two-way ANOVA followed by a post-hoc Fisher’s LSD test. DCX protein levels were significantly increased by IGF2 infusion [F(1, 20) = 15.828, p = 0.001]. Significant differences between groups, as determined by a post-hoc Fisher’s LSD test, are indicated by * (p = 0.005) and # (p = 0.022) (see brackets). Scale bar represents 50 µm.</p

IGF2 infusion increases cell size of BFCN in the septum, septal <i>Chat</i> mRNA levels and hippocampal CHAT protein levels.

<p>Septal sections from WT/CHGFP and APP.PS1/CHGFP mice were stained with anti-p75NGFR antibody and imaged using a confocal microscope (A) and mean fluorescence intensity of GFP in BFCN (B) and average BFCN size calculated (C). Septal lysates were analyzed by RT-PCR to determine <i>Chat</i> mRNA levels (D). Hippocampal lysates were used to determine CHAT protein levels by immunoblot (E). Data were analyzed by two-way ANOVA followed by a post-hoc Fisher’s LSD test. GFP mean intensity was significantly affected by the infusion of IGF2 [F(1, 20) = 20.589, p = 0.002] and genotype [F(1, 20) = 7.294, p = 0.014]. Significant differences in GFP intensity between groups are indicated by * (p = 0.016), # (p = 0.001), and † (p = 0.022) (B, see brackets). The area of GFP-positive cells was also significantly influenced by IGF2 treatment [F(1, 20) = 8.770, p = 0.008] and genotype [F(1, 20) = 4.695, p = 0.043]. Significant differences in average area between groups are indicated by * (p = 0.014) and # (p = 0.035) (C, see brackets). IGF2 infusion also significantly increased the expression of CHAT mRNA [F(1, 20) = 5.120, p = 0.035] and protein [F(1, 20) = 29.956, p = 0.0001]. Significant differences in CHAT protein levels between groups are indicated by * (p = 0.004) and # (p = 0.006) (G, see brackets). Scale bar represents 50 µm.</p