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

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). www.fasebj.org

[1]  E. Mufson,et al.  Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer's disease , 2019, Hippocampus.

[2]  J. Blusztajn,et al.  Choline , 2018, Nutrition Today.

[3]  J. Herbert,et al.  Efficacy of Maternal Choline Supplementation During Pregnancy in Mitigating Adverse Effects of Prenatal Alcohol Exposure on Growth and Cognitive Function: A Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial , 2018, Alcoholism, clinical and experimental research.

[4]  J. Jacobson,et al.  Feasibility and Acceptability of Maternal Choline Supplementation in Heavy Drinking Pregnant Women: A Randomized, Double‐Blind, Placebo‐Controlled Clinical Trial , 2018, Alcoholism, clinical and experimental research.

[5]  Sang Han Lee,et al.  CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation , 2018, Hippocampus.

[6]  J. Grenier,et al.  Maternal Choline Supplementation during Normal Murine Pregnancy Alters the Placental Epigenome: Results of an Exploratory Study , 2018, Nutrients.

[7]  Sang Han Lee,et al.  Expression profiling suggests microglial impairment in human immunodeficiency virus neuropathogenesis , 2018, Annals of neurology.

[8]  R. Canfield,et al.  Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double‐blind, controlled feeding study , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  S. Barger,et al.  Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs , 2017, Alzheimer's & Dementia.

[10]  Saadia Zahid,et al.  A review of the role of synaptosomal-associated protein 25 (SNAP-25) in neurological disorders , 2017, The International journal of neuroscience.

[11]  Daniela A. Recabarren,et al.  Gene networks in neurodegenerative disorders. , 2017, Life sciences.

[12]  J. Blusztajn,et al.  Neuroprotective Actions of Dietary Choline , 2017, Nutrients.

[13]  Laura Cancedda,et al.  The GABAergic Hypothesis for Cognitive Disabilities in Down Syndrome , 2017, Front. Cell. Neurosci..

[14]  Anita G. Ganti,et al.  Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women Consuming Choline Intakes Meeting Current Recommendations , 2017, International journal of molecular sciences.

[15]  E. Mufson,et al.  Maternal choline supplementation in a mouse model of Down syndrome: Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring , 2017, Neuroscience.

[16]  E. Mufson,et al.  Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome , 2016, Brain Structure and Function.

[17]  A. Dhanasekaran,et al.  Mouse models of Down syndrome: gene content and consequences , 2016, Mammalian Genome.

[18]  D. Zheng,et al.  DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative‐associated proteins , 2016, The EMBO journal.

[19]  C. Chio,et al.  Neuron-derived orphan receptor 1 transduces survival signals in neuronal cells in response to hypoxia-induced apoptotic insults. , 2016, Journal of neurosurgery.

[20]  Yifeng Du,et al.  Glutamatergic and central cholinergic dysfunction in the CA1, CA2 and CA3 fields on spatial learning and memory in chronic cerebral ischemia—Induced vascular dementia of rats , 2016, Neuroscience Letters.

[21]  L. Ouyang,et al.  Unraveling the roles of Atg4 proteases from autophagy modulation to targeted cancer therapy. , 2016, Cancer letters.

[22]  S. Chandra,et al.  Neuronal ceroid lipofuscinosis with DNAJC5/CSPα mutation has PPT1 pathology and exhibit aberrant protein palmitoylation , 2016, Acta Neuropathologica.

[23]  D. Barros,et al.  Regulation of Cognitive Processing by Hippocampal Cholinergic Tone , 2016, Cerebral cortex.

[24]  E. Mufson,et al.  Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer's Disease. , 2015, Current Alzheimer research.

[25]  E. Mufson,et al.  Effects of Maternal Choline Supplementation on the Septohippocampal Cholinergic System in the Ts65Dn Mouse Model of Down Syndrome. , 2015, Current Alzheimer research.

[26]  M. F. Falangola,et al.  Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome. , 2015, Current Alzheimer research.

[27]  L. Guilhoto,et al.  Cerebal overinhibition could be the basis for the high prevalence of epilepsy in persons with Down syndrome , 2015, Epilepsy & Behavior.

[28]  John Calvin Reed,et al.  ATG4B (Autophagin-1) Phosphorylation Modulates Autophagy* , 2015, The Journal of Biological Chemistry.

[29]  M. Caudill,et al.  Choline intakes exceeding recommendations during human lactation improve breast milk choline content by increasing PEMT pathway metabolites. , 2015, The Journal of nutritional biochemistry.

[30]  Sang Han Lee,et al.  Expression profile analysis of hippocampal CA1 pyramidal neurons in aged Ts65Dn mice, a model of Down syndrome (DS) and Alzheimer’s disease (AD) , 2015, Brain Structure and Function.

[31]  A. Heguy,et al.  Calorie Restriction Suppresses Age-Dependent Hippocampal Transcriptional Signatures , 2015, PloS one.

[32]  Alan Sharpe,et al.  High-Frequency Targetable EGFR Mutations in Sinonasal Squamous Cell Carcinomas Arising from Inverted Sinonasal Papilloma. , 2015, Cancer research.

[33]  S. Strittmatter,et al.  Fyn inhibition rescues established memory and synapse loss in Alzheimer mice , 2015, Annals of neurology.

[34]  M. Carrillo,et al.  Down syndrome and Alzheimer's disease: Common pathways, common goals , 2015, Alzheimer's & Dementia.

[35]  R. Minghim,et al.  InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams , 2015, BMC Bioinformatics.

[36]  A. Contestabile,et al.  Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome , 2015, Nature Medicine.

[37]  E. Choi,et al.  Compromised MAPK signaling in human diseases: an update , 2015, Archives of Toxicology.

[38]  S. Ginsberg,et al.  Maternal choline supplementation programs greater activity of the phosphatidylthanolamine N‐methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  E. Mufson,et al.  Maternal choline supplementation improves spatial mapping and increases basal forebrain cholinergic neuron number and size in aged Ts65Dn mice , 2014, Neurobiology of Disease.

[40]  Sterling C. Johnson,et al.  Cognitive functioning in relation to brain amyloid-β in healthy adults with Down syndrome. , 2014, Brain : a journal of neurology.

[41]  E. Mufson,et al.  Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young‐adult Ts65Dn and disomic mice , 2014, The Journal of comparative neurology.

[42]  J. Maguire,et al.  The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type , 2014, Front. Neural Circuits.

[43]  Jonas Christoffersson,et al.  Autophagy and apoptosis dysfunction in neurodegenerative disorders , 2014, Progress in Neurobiology.

[44]  E. Mufson,et al.  Sex Differences in the Cholinergic Basal Forebrain in the Ts65Dn Mouse Model of Down Syndrome and Alzheimer's Disease , 2014, Brain pathology.

[45]  D. Klionsky,et al.  The machinery of macroautophagy , 2013, Cell Research.

[46]  A. Jalanko,et al.  Cell biology and function of neuronal ceroid lipofuscinosis-related proteins. , 2013, Biochimica et biophysica acta.

[47]  B. Bogerts,et al.  Wide distribution of CREM immunoreactivity in adult and fetal human brain, with an increased expression in dentate gyrus neurons of Alzheimer’s as compared to normal aging brains , 2013, Amino Acids.

[48]  E. Mufson,et al.  Maternal choline supplementation improves spatial learning and adult hippocampal neurogenesis in the Ts65Dn mouse model of Down syndrome , 2013, Neurobiology of Disease.

[49]  S. Zeisel Nutrition in pregnancy: the argument for including a source of choline , 2013, International journal of women's health.

[50]  J. Blusztajn,et al.  Neuroprotective actions of perinatal choline nutrition , 2013, Clinical chemistry and laboratory medicine.

[51]  R. Freedman,et al.  Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. , 2013, The American journal of psychiatry.

[52]  J. Reznick,et al.  Phosphatidylcholine supplementation in pregnant women consuming moderate-choline diets does not enhance infant cognitive function: a randomized, double-blind, placebo-controlled trial. , 2012, The American journal of clinical nutrition.

[53]  P. Conn,et al.  Emerging approaches for treatment of schizophrenia: modulation of cholinergic signaling. , 2012, Discovery medicine.

[54]  J. Mill,et al.  Analysis of SNAP25 mRNA expression and promoter DNA methylation in brain areas of Alzheimer’s Disease patients , 2012, Neuroscience.

[55]  X. Hou,et al.  Fyn Kinases Play a Critical Role in Neuronal Apoptosis Induced by Oxygen and Glucose Deprivation or Amyloid‐β Peptide Treatment , 2012, CNS neuroscience & therapeutics.

[56]  P. Vandenabeele,et al.  Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke , 2012, Proceedings of the National Academy of Sciences.

[57]  Di Chen,et al.  Novel epigallocatechin gallate (EGCG) analogs activate AMP-activated protein kinase pathway and target cancer stem cells. , 2012, Bioorganic & medicinal chemistry.

[58]  T. Südhof,et al.  CSPα knockout causes neurodegeneration by impairing SNAP‐25 function , 2012, The EMBO journal.

[59]  S. Ginsberg,et al.  Microarray analysis of CA1 pyramidal neurons in a mouse model of tauopathy reveals progressive synaptic dysfunction , 2012, Neurobiology of Disease.

[60]  J. Schuchhardt,et al.  Evidence for Elevated Cerebrospinal Fluid ERK1/2 Levels in Alzheimer Dementia , 2011, International journal of Alzheimer's disease.

[61]  Y. Hérault,et al.  Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling down syndrome , 2011, Mammalian Genome.

[62]  K. Gardiner,et al.  Transcript catalogs of human chromosome 21 and orthologous chimpanzee and mouse regions , 2011, Mammalian Genome.

[63]  L. Mucke,et al.  Amyloid-β/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer's Disease , 2011, The Journal of Neuroscience.

[64]  R. Neve,et al.  Microarray Analysis of Hippocampal CA1 Neurons Implicates Early Endosomal Dysfunction During Alzheimer's Disease Progression , 2010, Biological Psychiatry.

[65]  S. Yen,et al.  Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathy , 2010, Neuropathology and applied neurobiology.

[66]  T. Südhof,et al.  α-Synuclein Promotes SNARE-Complex Assembly in Vivo and in Vitro , 2010, Science.

[67]  S. Ginsberg Alterations in discrete glutamate receptor subunits in adult mouse dentate gyrus granule cells following perforant path transection , 2010, Analytical and bioanalytical chemistry.

[68]  E. Morselli,et al.  Autophagy regulation by p53. , 2010, Current opinion in cell biology.

[69]  Kerry A. Mullaney,et al.  Alzheimer’s-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition , 2009, Proceedings of the National Academy of Sciences.

[70]  Y. Matsuoka,et al.  In Vivo Turnover of Tau and APP Metabolites in the Brains of Wild-Type and Tg2576 Mice: Greater Stability of sAPP in the β-Amyloid Depositing Mice , 2009, PloS one.

[71]  S. Ginsberg,et al.  Terminal continuation (TC) RNA amplification without second strand synthesis , 2009, Journal of Neuroscience Methods.

[72]  E. Masliah,et al.  Excitatory‐inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of down syndrome , 2009, The Journal of comparative neurology.

[73]  S. Ginsberg,et al.  Terminal Continuation (TC) RNA Amplification Enables Expression Profiling Using Minute RNA Input Obtained from Mouse Brain , 2008, International journal of molecular sciences.

[74]  J. Blusztajn,et al.  Prenatal choline supplementation in rats increases the expression of IGF2 and its receptor IGF2R and enhances IGF2-induced acetylcholine release in hippocampus and frontal cortex , 2008, Brain Research.

[75]  Michael J. Meaney,et al.  Diet and the epigenetic (re)programming of phenotypic differences in behavior , 2008, Brain Research.

[76]  L. Gan,et al.  Cystatin C-Cathepsin B Axis Regulates Amyloid Beta Levels and Associated Neuronal Deficits in an Animal Model of Alzheimer's Disease , 2008, Neuron.

[77]  E. Mufson,et al.  Galanin Hyperinnervation Upregulates Choline Acetyltransferase Expression in Cholinergic Basal Forebrain Neurons in Alzheimer’s Disease , 2008, Neurodegenerative Diseases.

[78]  D. Panagiotakos,et al.  Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study. , 2008, The American journal of clinical nutrition.

[79]  J. Blusztajn,et al.  Prenatal choline deficiency increases choline transporter expression in the septum and hippocampus during postnatal development and in adulthood in rats , 2007, Brain Research.

[80]  Fabian Fernandez,et al.  Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome , 2007, Nature Neuroscience.

[81]  B. Efron Correlation and Large-Scale Simultaneous Significance Testing , 2007 .

[82]  J. Wuu,et al.  Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease , 2006, Journal of neurochemistry.

[83]  S. Shimizu,et al.  Hippocampal vulnerability following traumatic brain injury: a potential role for neurotrophin‐4/5 in pyramidal cell neuroprotection , 2006, The European journal of neuroscience.

[84]  S. Ginsberg Glutamatergic neurotransmission expression profiling in the mouse hippocampus after perforant-path transection. , 2005, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[85]  S. Ginsberg,et al.  RNA amplification strategies for small sample populations. , 2005, Methods.

[86]  C. Epstein,et al.  Synaptic structural abnormalities in the Ts65Dn mouse model of down syndrome , 2004, The Journal of comparative neurology.

[87]  J. Loeffler,et al.  Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders. , 2004, Biochemical pharmacology.

[88]  A. Yamamoto,et al.  LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation , 2004, Journal of Cell Science.

[89]  W. Meck,et al.  Prenatal choline supplementation advances hippocampal development and enhances MAPK and CREB activation , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[90]  Katheleen Gardiner,et al.  Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions. , 2003, Gene.

[91]  R. Reeves,et al.  Global disruption of the cerebellar transcriptome in a Down syndrome mouse model. , 2003, Human molecular genetics.

[92]  N. J. Sandstrom,et al.  Prenatal choline supplementation increases NGF levels in the hippocampus and frontal cortex of young and adult rats , 2002, Brain Research.

[93]  B T Hyman,et al.  Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. , 2000, The American journal of pathology.

[94]  D. Davies,et al.  Synaptic deficit in the temporal cortex of partial trisomy 16 (Ts65Dn) mice , 2000, Brain Research.

[95]  J. Kordower,et al.  Reduction in TrkA‐Immunoreactive Neurons Is Not Associated with an Overexpression of Galaninergic Fibers Within the Nucleus Basalis in Down's Syndrome , 2000, Journal of neurochemistry.

[96]  A. Granholm,et al.  Loss of Cholinergic Phenotype in Basal Forebrain Coincides with Cognitive Decline in a Mouse Model of Down's Syndrome , 2000, Experimental Neurology.

[97]  A. M. Insausti,et al.  Hippocampal volume and neuronal number in Ts65Dn mice: a murine model of down syndrome , 1998, Neuroscience Letters.

[98]  J. Blusztajn,et al.  Choline, a Vital Amine , 1998, Science.

[99]  M. Raskind,et al.  Early Amyloid Deposition in the Medial Temporal Lobe of Young Down Syndrome Patients: A Regional Quantitative Analysis , 1998, Experimental Neurology.

[100]  D. Holtzman,et al.  Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[101]  W. Meck,et al.  Organizational changes in cholinergic activity and enhanced visuospatial memory as a function of choline administered prenatally or postnatally or both. , 1989, Behavioral neuroscience.

[102]  R. S. Williams,et al.  A prospective study of Alzheimer disease in Down syndrome. , 1989, Archives of neurology.

[103]  P. Yates,et al.  THE TOPOGRAPHY OF PLAQUES AND TANGLES IN DOWN'S SYNDROME PATIENTS OF DIFFERENT AGES , 1986, Neuropathology and applied neurobiology.

[104]  H. Wiśniewski,et al.  Alzheimer's disease in Down's syndrome , 1985, Neurology.

[105]  M. Gwee,et al.  FREE CHOLINE CONCENTRATION AND CEPHALIN‐N‐METHYLTRANSFERASE ACTIVITY IN THE MATERNAL AND FOETAL LIVER AND PLACENTA OF PREGNANT RATS , 1978, Clinical and experimental pharmacology & physiology.

[106]  C. Breedon,et al.  Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts 65 Dn mouse model of Down syndrome , 2017 .

[107]  Sang Han Lee,et al.  Expression profile analysis of vulnerable CA1 pyramidal neurons in young–Middle‐Aged Ts65Dn mice , 2015, The Journal of comparative neurology.

[108]  M. Kindy,et al.  Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic. , 2014, Journal of Alzheimer's disease : JAD.

[109]  Isidro Ferrer,et al.  Neuron-specific alterations in signal transduction pathways associated with Alzheimer's disease. , 2014, Journal of Alzheimer's disease : JAD.

[110]  S. Ginsberg Considerations in the Use of Microarrays for Analysis of the CNS , 2014 .

[111]  M. Kindy,et al.  Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing AβPP containing the wild-type β-secretase site sequence. , 2012, Journal of Alzheimer's disease : JAD.

[112]  T. Südhof,et al.  CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity , 2011, Nature Cell Biology.

[113]  T. Südhof,et al.  CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity , 2011, Nature Cell Biology.

[114]  M. Strawderman,et al.  Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts65Dn mouse model of Down syndrome. , 2010, Behavioral neuroscience.

[115]  E. Mufson,et al.  Galanin fiber hyperinnervation preserves neuroprotective gene expression in cholinergic basal forebrain neurons in Alzheimer's disease. , 2009, Journal of Alzheimer's disease : JAD.

[116]  S. Ginsberg Transcriptional profiling of small samples in the central nervous system. , 2008, Methods in molecular biology.

[117]  S. Ginsberg,et al.  Amplification of RNA transcripts using terminal continuation , 2004, Laboratory Investigation.

[118]  A. Granholm,et al.  Estrogen alters amyloid precursor protein as well as dendritic and cholinergic markers in a mouse model of Down syndrome , 2003, Hippocampus.

[119]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .