Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer's Disease

Abstract

Although Down syndrome (DS) can be diagnosed prenatally, currently there are no effective treatments to lessen the intellectual disability (ID) which is a hallmark of this disorder. Furthermore, starting as early as the third decade of life, DS individuals exhibit the neuropathological hallmarks of Alzheimer's disease (AD) with subsequent dementia, adding substantial emotional and financial burden to their families and society at large. A potential therapeutic strategy emerging from the study of trisomic mouse models of DS is to supplement the maternal diet with additional choline during pregnancy and lactation. Studies demonstrate that maternal choline supplementation (MCS) markedly improves spatial cognition and attentional function, as well as normalizes adult hippocampal neurogenesis and offers protection to basal forebrain cholinergic neurons (BFCNs) in the Ts65Dn mouse model of DS. These effects on neurogenesis and BFCNs correlate significantly with spatial cognition, suggesting functional relationships. In this review, we highlight some of these provocative findings, which suggest that supplementing the maternal diet with additional choline may serve as an effective and safe prenatal strategy for improving cognitive, affective, and neural functioning in DS. In light of growing evidence that all pregnancies would benefit from increased maternal choline intake, this type of recommendation could be given to all pregnant women, thereby providing a very early intervention for individuals with DS, and include babies born to mothers unaware that they are carrying a fetus with DS.

Figure 1

Effects of MCS on attentional function and emotional reactivity. A: Mean (+/−SE) percentage of correct responses, as a function of the four session blocks (five sessions/block) on the first attention task in which a variable delay was imposed before cue presentation. Although the four groups did not differ in the first session block, differences emerged during the last three session blocks. During these latter 15 sessions, the unsupplemented Ts65Dn mice performed significantly worse than both groups of 2N mice. In contrast, the choline-supplemented Ts65Dn mice did not differ from the unsupplemented 2N mice for any session-block, and performed better than their unsupplemented counterpart mice for Session Blocks 2 and 3. The choline-supplemented 2N mice performed significantly better than their unsupplemented counterparts during Session Block 2. B: Mean (+/−SE) percentage of correct responses as a function of the pre-cue delay, in a task in which both cue duration and pre-cue delay varied across trials. The unsupplemented Ts65Dn mice performed significantly worse than the unsupplemented 2N controls at all delays. In contrast, the choline-supplemented Ts65Dn mice performed significantly better than their unsupplemented counterparts for trials with a 0-s (p < 0.002) or 4-s (p < 0.02) pre-cue delay, and did not differ significantly from the 2N mice for any delay. C: Mean (+/−SE) percentage of trials on which the mice exhibited a long latency (≥ 5 s) to initiate the next trial, referred to as alcove latency (AL), as a function of the outcome of the previous trial (correct or incorrect). No group differences were seen for trials that followed a correct response (PREV CORRECT). However, for trials that followed an error (PREV ERROR), the incidence of trials with a long initiation latency was significantly greater for the unsupplemented trisomic mice than for the two groups of 2N mice and the supplemented trisomic mice. *, p < 0.05, compared with the unsupplemented Ts65Dn mice. Adapted from Moon et al., 2010 [75], and revised images used with permission

Figure 2

MCS effects on spatial cognition, hippocampal neurogenesis, and BFCN density. A: Average errors per trial (collapsed across sessions) in the Hidden Platform (HP) task of the radial arm water maze (RAWM), a task which requires spatial mapping. Mean errors per trial were significantly higher for the unsupplemented Ts65Dn mice than their 2N counterparts. MCS significantly improved performance for Ts65Dn (p = 0.011). B: Mean errors per trial in the HP task, shown as a function of session-block (3 sessions/block). C: Mean (±SE) number of DCX-positive cells in the dentate gyrus. Unsupplemented Ts65Dn mice displayed significantly fewer DCX-positive cells than 2N mice (p<0.0001). MCS significantly increased the number of DCX-positive cells in Ts65Dn mice (p<0.001). D: The number of DCX-positive cells in the dentate gyrus of the hippocampus was a significant predictor of performance in the HP task, an index of spatial learning/memory. E: Ts65Dn mice showed a significantly lower ChAT-ir density relative to 2N mice (p = 0.008). MCS significantly increased the density of ChAT-ir neurons in Ts65Dn mice (p = 0.036). F: Density of ChAT-ir neurons in the MSN was a significant predictor of performance in the HP task. Adapted from Ash et al., 2014 and Velazquez et al., 2013 [74, 76], and revised images used with permission.

Figure 3

Effects of MCS on choline metabolites in Ts65Dn mice and 2N littermates. A: Schematic of the metabolism of the orally consumed d9-choline tracer. Intact d9-choline can be used to produce these d9-choline metabolites: d9-acetylcholine (d9-ACho), d9-betaine (d9-Bet), d9-phosphocholine (d9-PCho), d9-glycerophosphocholine (d9-GPC) and d9-phosphatidylcholine (d9-PC). Alternatively, the d9-choline tracer can be oxidized to d9-betaine and one of its three methyl groups can be donated to homocysteine (Hcy) forming d3-methionine (d3-Met) and subsequently d3-S-adenosylmethionine (d3-SAM). A main consumer of SAM is the phosphatidylethanolamine N-methyltransferase (PEMT) pathway which mediates the sequential methylation of phosphatidylethanolamine (PE) to PC (phosphatidylcholine). Under the current labeling strategy, the PEMT pathway generated d3-PC and d6-PC. These PEMT-PC labeled metabolites can then undergo hydrolysis to synthesize other metabolites including d3-ACho, d3-Bet, d3-PCho, and d3-GPC). B: Effects of MCS on overall d3+d6-enrichment in liver, plasma, and brain regions including basal forebrain, hippocampus, neocortex, and cerebellum of adult Ts65Dn and 2N offspring born to unsupplemented (C) versus supplemented (MCS) dams. C: Effects of MCS on overall d9-enrichment in liver, plasma, and brain regions including hippocampus, neocortex, and cerebellum of adult Ts65Dn and 2N offspring born to choline unsupplemented as compared to choline supplemented dams. Key, B, C: *= p≤ 0.05, **= p≤ 0.01, and ***= p≤ 0.001. Adapted from Yan et al., 2014 [57], and revised images used with permission.