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 DS fetuses, and include babies born to mothers unaware that they are carrying a DS fetus.

Maternal choline supplementation in a mouse model of Down syndrome: Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring

“…Since functional deficits associated with DS correspond with endpoints affected by MCS, we previously conducted a study to test the hypothesis that MCS would improve learning and attention in Ts65Dn offspring. This study yielded evidence for substantial cognitive benefits, as well as an improved regulation of negative affect in Ts65Dn mice (Moon et al, 2010; Strupp et al, 2016). …”

“…Our group has demonstrated that supplementing the maternal diet with additional choline has numerous beneficial effects for Ts65Dn and 2N offspring, including improvements in attention, emotion regulation, spatial memory, hippocampal neurogenesis, and protection of cholinergic neurons in the MSN (Ash et al, 2014; Moon et al, 2010; Strupp et al, 2016; Velazquez et al, 2013). Choline supply is critical for the developing brain because it is a precursor of acetylcholine, a key neurotransmitter for regulating neuronal proliferation, differentiation, migration, maturation, plasticity, and survival, as well as synapse formation (Abreu-Villaca et al, 2011; Albright et al, 1999; Blusztajn, 1998; Cermak et al, 1999; Zeisel, 2011).…”

“…Our group has been investigating maternal choline supplementation (MCS) as a potential prenatal therapeutic strategy for DS (Strupp et al, 2016). Decades of research has revealed that in normal rodents supplementing the maternal diet with additional choline during gestation and/or lactation produces lifelong improvements in spatial cognition and attention of the offspring, as well as changes in MSN cholinergic neurons and electrophysiological indices of hippocampal function (Meck and Williams, 2003; Zeisel and Niculescu, 2006).…”

Effects of Maternal Choline Supplementation on the Septohippocampal Cholinergic System in the Ts65Dn Mouse Model of Down Syndrome

“…Organizational brain changes may result from choline’s role as the precursor to phosphatidylcholine, a major constituent of neuronal cellular membranes, and, to a lesser extent, as a precursor of ACh, which is a key ontogenetic signal during development [34,51,57,102]. Additionally, long-term effects of early choline supplementation may be related to epigenetic factors with lasting effects on gene expression, secondary to choline’s role as a methyl donor [39,103–105].…”

“…A potential treatment approach involves maternal dietary supplementation with choline, an essential nutrient involved in neural tube closure, organogenesis, central nervous system cell membrane synthesis, and methylation-dependent gene expression [36,38–44]. MCS has both immediate and long-term beneficial effects in healthy disomic rats and mice [44–57], and in rodent models of prenatal ethanol exposure, Rett syndrome, and status epilepticus [58–63]. To explore the effects of early choline supplementation on cholinergic innervation and activity in the hippocampus of the adult brain, we used a MCS paradigm and studied adult male Ts65Dn and 2N offspring.…”