Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

Abstract

Choline is critical for normative function of 3 major pathways in the brain, including acetylcholine biosynthesis, being a key mediator of epigenetic regulation, and serving as the primary substrate for the phosphatidylethanolamine N‐methyltransferase pathway. Sufficient intake of dietary choline is critical for proper brain function and neurodevelopment. This is especially important for brain development during the perinatal period. Current dietary recommendations for choline intake were undertaken without critical evaluation of maternal choline levels. As such, recommended levels may be insufficient for both mother and fetus. Herein, we examined the impact of perinatal maternal choline supplementation (MCS) in a mouse model of Down syndrome and Alzheimer's disease, the Ts65Dn mouse relative to normal disomic littermates, to examine the effects on gene expression within adult offspring at ∼6 and 11 mo of age. We found MCS produces significant changes in offspring gene expression levels that supersede age‐related and genotypic gene expression changes. Alterations due to MCS impact every gene ontology category queried, including GABAergic neurotransmission, the endosomal‐lysosomal pathway and autophagy, and neurotrophins, highlighting the importance of proper choline intake during the perinatal period, especially when the fetus is known to have a neurodevelopmental disorder such as trisomy.—Alldred, M. J., Chao, H. M., Lee, S. H., Beilin, J., Powers, B. E., Petkova, E., Strupp, B. J., Ginsberg, S. D. Long‐term effects of maternal choline supplementation on CA1 pyramidal neuron gene expression in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease. FASEB J. 33, 9871–9884 (2019). http://www.fasebj.org

Choline, Neurological Development and Brain Function: A Systematic Review Focusing on the First 1000 Days

“…Thirdly, there is now a well-established body of evidence from animal studies showing that higher choline intakes can ameliorate neurological damage associated with inherited conditions such as Down Syndrome, as well as potentially protecting the brain from the neuropathological changes associated with Alzheimer's Disease [43,[82][83][84][85][86]95,[106][107][108][109]137]. In particular, the scientific evidence shows that maternal choline supplementation protects basal forebrain cholinergic neurons and normalizes neurogenesis helping to improve cognition and attention in individuals with Down Syndrome, who can exhibit hallmarks of Alzheimer's Disease as early as the third decade of life [137,138].…”

“…Multiple animal studies [82][83][84][85][86][87] have observed positive effects of choline on neurogenesis, many of which have studied effects on neuron gene expression. Effects of choline on angiogenesis have also been observed.…”

“…Alldred et al (2019) [82] found that maternal choline supplementation in a mouse model of Alzheimer's disease and Down syndrome favorably altered the expression of genes involved in GABAergic neurotransmission and neurotrophins. This highlights the importance of adequate choline intake, particularly when the fetus has a neurodevelopmental disorder such as trisomy.…”

Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

“…Lately, we demonstrated that rescuing protein O-GlcNAcylation levels in Ts2Cje mice by intranasal Thiamet G administration (25μg/mouse; 2 times/day for 5 days) boosted autophagy induction favoring the restoration of proteostasis [ 56 ]. Alldred and colleagues in 2019 examined the impact of perinatal maternal choline supplementation in Ts65Dn mouse to discern the effects on gene expression within adult offspring at ~6 and 11 months of age [ 224 ]. The authors found that maternal choline supplementation (5.0 g/kg choline chloride) diet produced significant changes in offspring gene expression levels associated with age-related cognitive decline including the endosomal-lysosomal pathway and autophagy.…”

Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer’s Disease

“…BFCN loss and changes in hippocampal innervation are consistently reported in Ts65Dn mice > 10 MO (26,27,29,37,38). Expression level changes in trisomic mice have been limited to regional analysis (37,39) or speci c neuronal subtype assessment by microarrays (35,(40)(41)(42)(43)(44).…”