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1.
J Alzheimers Dis ; 63(4): 1433-1443, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29843236

RESUMO

The pathophysiology of Alzheimer's disease (AD) includes signaling defects mediated by the transforming growth factor ß-bone morphogenetic protein-growth and differentiation factor (TGFß-BMP-GDF) family of proteins. In animal models of AD, administration of BMP9/GDF2 improves memory and reduces amyloidosis. The best characterized type I receptor of BMP9 is ALK1. We characterized ALK1 expression in the hippocampus using immunohistochemistry. In the rat, ALK1 immunoreactivity was found in CA pyramidal neurons, most frequently and robustly in the CA2 and CA3 fields. In addition, there were sporadic ALK1-immunoreactive cells in the stratum oriens, mainly in CA1. The ALK1 expression pattern in human hippocampus was similar to that of rat. Pyramidal neurons within the CA2, CA3, and CA4 were strongly ALK1-immunoreactive in hippocampi of cognitively intact subjects with no neurofibrillary tangles. ALK1 signal was found in the axons of alveus and fimbria, and in the neuropil across CA fields. Relatively strongest ALK1 neuropil signal was observed in CA1 where pyramidal neurons were occasionally ALK1-immunoractive. As in the rat, horizontally oriented neurons in the stratum oriens of CA1 were both ALK1- and GAD67-immunoreactive. Analysis of ALK1 immunoreactivity across stages of AD pathology revealed that disease progression was characterized by overall reduction of the ALK1 signal in CA3 in advanced, but not early, stages of AD. These data suggest that the CA3 pyramidal neurons may remain responsive to the ALK1 ligands, e.g., BMP9, during initial stages of AD and that ALK1 may constitute a therapeutic target in early and moderate AD.


Assuntos
Receptores de Activinas Tipo II/metabolismo , Receptores de Ativinas/metabolismo , Doença de Alzheimer/patologia , Região CA3 Hipocampal/metabolismo , Progressão da Doença , Idoso , Doença de Alzheimer/metabolismo , Animais , Feminino , Glutamato Descarboxilase/metabolismo , Fatores de Diferenciação de Crescimento/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Ratos , Ratos Wistar
2.
Nutrients ; 9(8)2017 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-28788094

RESUMO

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.


Assuntos
Colina/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Colina/administração & dosagem , Cognição/efeitos dos fármacos , Dieta , Humanos , Fármacos Neuroprotetores/administração & dosagem
4.
PLoS One ; 12(1): e0170450, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28103298

RESUMO

Prevention of Alzheimer's disease (AD) is a major goal of biomedical sciences. In previous studies we showed that high intake of the essential nutrient, choline, during gestation prevented age-related memory decline in a rat model. In this study we investigated the effects of a similar treatment on AD-related phenotypes in a mouse model of AD. We crossed wild type (WT) female mice with hemizygous APPswe/PS1dE9 (APP.PS1) AD model male mice and maintained the pregnant and lactating dams on a control AIN76A diet containing 1.1 g/kg of choline or a choline-supplemented (5 g/kg) diet. After weaning all offspring consumed the control diet. As compared to APP.PS1 mice reared on the control diet, the hippocampus of the perinatally choline-supplemented APP.PS1 mice exhibited: 1) altered levels of amyloid precursor protein (APP) metabolites-specifically elevated amounts of ß-C-terminal fragment (ß-CTF) and reduced levels of solubilized amyloid Aß40 and Aß42 peptides; 2) reduced number and total area of amyloid plaques; 3) preserved levels of choline acetyltransferase protein (CHAT) and insulin-like growth factor II (IGF2) and 4) absence of astrogliosis. The data suggest that dietary supplementation of choline during fetal development and early postnatal life may constitute a preventive strategy for AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Precursor de Proteína beta-Amiloide/genética , Amiloidose/prevenção & controle , Colina O-Acetiltransferase/metabolismo , Colina/administração & dosagem , Suplementos Nutricionais , Hipocampo/metabolismo , Presenilina-1/genética , Doença de Alzheimer/dietoterapia , Precursor de Proteína beta-Amiloide/metabolismo , Amiloidose/patologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Camundongos , Camundongos Mutantes , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Neurogênese/efeitos dos fármacos , Gravidez , Presenilina-1/metabolismo
5.
Behav Brain Res ; 278: 210-20, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25300468

RESUMO

Autism is a neurodevelopmental disorder with multiple genetic and environmental risk factors. Choline is a fundamental nutrient for brain development and high choline intake during prenatal and/or early postnatal periods is neuroprotective. We examined the effects of perinatal choline supplementation on social behavior, anxiety, and repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse model of autism. The BTBR or the more "sociable" C57BL/6J (B6) strain females were fed a control or choline-supplemented diet from mating, throughout pregnancy and lactation. After weaning to a control diet, all offspring were evaluated at one or two ages [postnatal days 33-36 and 89-91] using open field (OF), elevated plus maze (EPM), marble burying (MB), and three-chamber social interaction tests. As expected, control-diet BTBR mice displayed higher OF locomotor activity, impaired social preference, and increased digging behavior during the MB test compared to control-diet B6 mice. Choline supplementation significantly decreased digging behavior, elevated the percentage of open arm entries and time spent in open arms in the EPM by BTBR mice, but had no effect on locomotion. Choline supplementation did not alter social interaction in B6 mice but remarkably improved impairments in social interaction in BTBR mice at both ages, indicating that the benefits of supplementation persist long after dietary choline returns to control levels. In conclusion, our results suggest that high choline intake during early development can prevent or dramatically reduce deficits in social behavior and anxiety in an autistic mouse model, revealing a novel strategy for the treatment/prevention of autism spectrum disorders.


Assuntos
Transtorno Autístico/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Colina/farmacologia , Nootrópicos/farmacologia , Animais , Ansiedade/tratamento farmacológico , Transtorno Autístico/psicologia , Colina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Atividade Motora/efeitos dos fármacos , Nootrópicos/administração & dosagem , Gravidez , Comportamento Social , Fatores de Tempo , Resultado do Tratamento
6.
PLoS One ; 9(4): e94287, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24732467

RESUMO

The development of an effective therapy for Alzheimer's disease (AD) is a major challenge to biomedical sciences. Because much of early AD pathophysiology includes hippocampal abnormalities, a viable treatment strategy might be to use trophic factors that support hippocampal integrity and function. IGF2 is an attractive candidate as it acts in the hippocampus to enhance memory consolidation, stimulate adult neurogenesis and upregulate cholinergic marker expression and acetylcholine (ACh) release. We performed a seven-day intracerebroventricular infusion of IGF2 in transgenic APPswe.PS1dE9 AD model mice that express green fluorescent protein in cholinergic neurons (APP.PS1/CHGFP) and in wild type WT/CHGFP littermates at 6 months of age representing early AD-like disease. IGF2 reduced the number of hippocampal Aß40- and Aß42-positive amyloid plaques in APP.PS1/CHGFP mice. Moreover, IGF2 increased hippocampal protein levels of the ACh-synthesizing enzyme, choline acetyltransferase in both WT/CHGFP and APP.PS1/CHGFP mice. The latter effect was likely mediated by increased protein expression of the cholinergic differentiating factor, BMP9, observed in IGF2-treated mice as compared to controls. IGF2 also increased the protein levels of hippocampal NGF, BDNF, NT3 and IGF1 and of doublecortin, a marker of neurogenesis. These data show that IGF2 administration is effective in reversing and preventing several pathophysiologic processes associated with AD and suggest that IGF2 may constitute a therapeutic target for AD.


Assuntos
Doença de Alzheimer/metabolismo , Amiloidose/patologia , Neurônios Colinérgicos/metabolismo , Fator 2 de Diferenciação de Crescimento/metabolismo , Hipocampo/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Fatores de Crescimento Neural/metabolismo , Receptores de Ativinas Tipo I/metabolismo , Receptores de Activinas Tipo II , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Amiloidose/complicações , Amiloidose/fisiopatologia , Animais , Biomarcadores/metabolismo , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/patologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/complicações , Gliose/patologia , Gliose/fisiopatologia , Hipocampo/enzimologia , Hipocampo/patologia , Humanos , Fator de Crescimento Insulin-Like II/administração & dosagem , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese , Neuropeptídeos/metabolismo , Placa Amiloide/complicações , Placa Amiloide/patologia , Placa Amiloide/fisiopatologia
7.
Proc Natl Acad Sci U S A ; 110(48): 19567-72, 2013 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-24218590

RESUMO

Bone morphogenetic protein 9 (BMP9) promotes the acquisition of the cholinergic phenotype in basal forebrain cholinergic neurons (BFCN) during development and protects these neurons from cholinergic dedifferentiation following axotomy when administered in vivo. A decline in BFCN function occurs in patients with Alzheimer's disease (AD) and contributes to the AD-associated memory deficits. We infused BMP9 intracerebroventricularly for 7 d in transgenic AD model mice expressing green fluorescent protein specifically in cholinergic neurons (APP.PS1/CHGFP) and in wild-type littermate controls (WT/CHGFP). We used 5-mo-old mice, an age when the AD transgenics display early amyloid deposition and few cholinergic defects, and 10-mo-old mice, by which time these mice exhibit established disease. BMP9 infusion reduced the number of Aß42-positive amyloid plaques in the hippocampus and cerebral cortex of 5- and 10-mo-old APP.PS1/CHGFP mice and reversed the reductions in choline acetyltransferase protein levels in the hippocampus of 10-mo-old APP.PS1/CHGFP mice. The treatment increased cholinergic fiber density in the hippocampus of both WT/CHGFP and APP.PS1/CHGFP mice at both ages. BMP9 infusion also increased hippocampal levels of neurotrophin 3, insulin-like growth factor 1, and nerve growth factor and of the nerve growth factor receptors, tyrosine kinase receptor A and p75/NGFR, irrespective of the genotype of the mice. These data show that BMP9 administration is effective in reducing the Aß42 amyloid plaque burden, reversing cholinergic neuron abnormalities, and generating a neurotrophic milieu for BFCN in a mouse model of AD and provide evidence that the BMP9-signaling pathway may constitute a therapeutic target for AD.


Assuntos
Doença de Alzheimer/metabolismo , Amiloidose/metabolismo , Neurônios Colinérgicos/metabolismo , Fator 2 de Diferenciação de Crescimento/farmacologia , Análise de Variância , Animais , Neurônios Colinérgicos/efeitos dos fármacos , Feminino , Fator 2 de Diferenciação de Crescimento/administração & dosagem , Fator 2 de Diferenciação de Crescimento/metabolismo , Imunoensaio , Immunoblotting , Imuno-Histoquímica , Masculino , Camundongos , Microscopia de Fluorescência
8.
Clin Chem Lab Med ; 51(3): 591-9, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23314544

RESUMO

Choline is an essential nutrient for humans. Studies in rats and mice have shown that high choline intake during gestation or the perinatal period improves cognitive function in adulthood, prevents memory decline of old age, and protects the brain from damage and cognitive and neurological deterioration associated with epilepsy and hereditary conditions such as Down's and Rett syndromes. These behavioral changes are accompanied by modified patterns of expression of hundreds of cortical and hippocampal genes including those encoding proteins central for learning and memory processing. The effects of choline correlate with cerebral cortical changes in DNA and histone methylation, thus suggesting an epigenomic mechanism of action of perinatal choline.


Assuntos
Encéfalo/efeitos dos fármacos , Colina/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Encéfalo/metabolismo , Colina/uso terapêutico , DNA/metabolismo , Epilepsia/tratamento farmacológico , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histonas/metabolismo , Humanos , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico
9.
Cent Nerv Syst Agents Med Chem ; 12(2): 82-94, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22483275

RESUMO

Choline is an essential nutrient for humans. Metabolically choline is used for the synthesis of membrane phospholipids (e.g. phosphatidylcholine), as a precursor of the neurotransmitter acetylcholine, and, following oxidation to betaine, choline functions as a methyl group donor in a pathway that produces S-adenosylmethionine. As a methyl donor choline influences DNA and histone methylation--two central epigenomic processes that regulate gene expression. Because the fetus and neonate have high demands for choline, its dietary intake during pregnancy and lactation is particularly important for normal development of the offspring. Studies in rodents have shown that high choline intake during gestation improves cognitive function in adulthood and prevents memory decline associated with old age. These behavioral changes are accompanied by electrophysiological, neuroanatomical, and neurochemical changes and by altered patterns of expression of multiple cortical and hippocampal genes including those encoding key proteins that contribute to the biochemical mechanisms of learning and memory. These actions of choline are observed long after the exposure to the nutrient ended (months) and correlate with fetal hepatic and cerebral cortical choline-evoked changes in global- and gene-specific DNA cytosine methylation and with dramatic changes of the methylation pattern of lysine residues 4, 9 and 27 of histone H3. Moreover, gestational choline modulates the expression of DNA (Dnmt1, Dnmt3a) and histone (G9a/Ehmt2/Kmt1c, Suv39h1/Kmt1a) methyltransferases. In addition to the central role of DNA and histone methylation in brain development, these processes are highly dynamic in adult brain, modulate the expression of genes critical for synaptic plasticity, and are involved in mechanisms of learning and memory. A recent study documented that in a cohort of normal elderly people, verbal and visual memory function correlated positively with the amount of dietary choline consumption. It will be important to determine if these actions of choline on human cognition are mediated by epigenomic mechanisms or by its influence on acetylcholine or phospholipid synthesis.


Assuntos
Encéfalo/crescimento & desenvolvimento , Colina/administração & dosagem , Colina/metabolismo , Metilação de DNA/fisiologia , Histonas/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Deficiência de Colina/dietoterapia , Deficiência de Colina/metabolismo , Deficiência de Colina/prevenção & controle , Feminino , Humanos , Estado Nutricional/fisiologia , Gravidez
10.
Brain Res ; 1413: 84-97, 2011 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-21840511

RESUMO

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12-17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury.


Assuntos
Deficiência de Colina/metabolismo , Colina/administração & dosagem , Hipocampo/metabolismo , Ácido Caínico/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Convulsões/metabolismo , Fatores Etários , Animais , Deficiência de Colina/induzido quimicamente , Suscetibilidade a Doenças , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/administração & dosagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente
11.
PLoS One ; 6(6): e21166, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21695154

RESUMO

BACKGROUND: Cholinergic projection from the septum to the hippocampus is crucial for normal cognitive function and degeneration of cells and nerve fibers within the septohippocampal pathway contributes to the pathophysiology of Alzheimer's disease. Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether BMP9 could protect the adult cholinergic septohippocampal pathway from axotomy-evoked loss of the cholinergic phenotype, we performed unilateral fimbria-fornix transection in mice and treated them with a continuous intracerebroventricular infusion of BMP9 for six days. The number of choline acetyltransferase (CHAT)-positive cells was reduced by 50% in the medial septal nucleus ipsilateral to the lesion as compared to the intact, contralateral side, and BMP9 infusion prevented this loss in a dose-dependent manner. Moreover, BMP9 prevented most of the decline of hippocampal acetylcholine levels ipsilateral to the lesion, and markedly increased CHAT, choline transporter CHT, NGF receptors p75 (NGFR-p75) and TrkA (NTRK1), and NGF protein content in both the lesioned and unlesioned hippocampi. In addition, BMP9 infusion reduced bilaterally hippocampal levels of basic FGF (FGF2) protein. CONCLUSIONS/SIGNIFICANCE: These data indicate that BMP9 administration can prevent lesion-evoked impairment of the cholinergic septohippocampal neurons in adult mice and, by inducing NGF, establishes a trophic environment for these cells.


Assuntos
Acetilcolina/metabolismo , Fatores de Diferenciação de Crescimento/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenótipo , Septo do Cérebro/citologia , Acetilcolina/biossíntese , Animais , Axotomia , Biomarcadores/metabolismo , Colina O-Acetiltransferase/metabolismo , Fórnice/cirurgia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Fatores de Diferenciação de Crescimento/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Bombas de Infusão , Masculino , Camundongos , Fator de Crescimento Neural/metabolismo , Neurônios/enzimologia , Receptor de Fator de Crescimento Neural/metabolismo , Receptor trkA/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
Hippocampus ; 21(6): 584-608, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20232399

RESUMO

Status epilepticus (SE) in adulthood dramatically alters the hippocampus and produces spatial learning and memory deficits. Some factors, like environmental enrichment and exercise, may promote functional recovery from SE. Prenatal choline supplementation (SUP) also protects against spatial memory deficits observed shortly after SE in adulthood, and we have previously reported that SUP attenuates the neuropathological response to SE in the adult hippocampus just 16 days after SE. It is unknown whether SUP can ameliorate longer-term cognitive and neuropathological consequences of SE, whether repeatedly engaging the injured hippocampus in a cognitive task might facilitate recovery from SE, and whether our prophylactic prenatal dietary treatment would enable the injured hippocampus to more effectively benefit from cognitive rehabilitation. To address these issues, adult offspring from rat dams that received either a control (CON) or SUP diet on embryonic days 12-17 first received training on a place learning water maze task (WM) and were then administered saline or kainic acid (KA) to induce SE. Rats then either remained in their home cage, or received three additional WM sessions at 3, 6.5, and 10 weeks after SE to test spatial learning and memory retention. Eleven weeks after SE, the brains were analyzed for several hippocampal markers known to be altered by SE. SUP attenuated SE-induced spatial learning deficits and completely rescued spatial memory retention by 10 weeks post-SE. Repeated WM experience prevented SE-induced declines in glutamic acid decarboxylase (GAD) and dentate gyrus neurogenesis, and attenuated increased glial fibrilary acidic protein (GFAP) levels. Remarkably, SUP alone was similarly protective to an even greater extent, and SUP rats that were water maze trained after SE showed reduced hilar migration of newborn neurons. These findings suggest that prophylactic SUP is protective against the long-term cognitive and neuropathological effects of KA-induced SE, and that rehabilitative cognitive enrichment may be partially beneficial.


Assuntos
Colina/administração & dosagem , Hipocampo , Ácido Caínico/efeitos adversos , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Estado Epiléptico , Animais , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Glutamato Descarboxilase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/patologia , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Neurônios/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Sprague-Dawley , /efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologia , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/dietoterapia , Estado Epiléptico/patologia , Estado Epiléptico/prevenção & controle
13.
J Neurosci ; 30(24): 8221-8, 2010 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-20554873

RESUMO

Acetylcholine (ACh) synthesis and release from basal forebrain cholinergic neurons (BFCN) innervating the cerebral cortex and hippocampus are essential processes for normal learning, memory and attention. Bone morphogenetic protein (BMP) 9 is a cholinergic differentiation factor in the developing septum that increases ACh synthesis and choline acetyltransferase (Chat) gene expression both in vivo and in vitro. We investigated the possible induction of cholinergic trophic factors by BMP9 in murine septal cells. Nerve growth factor (NGF) protein expression and secretion into the medium was increased in cultured embryonic septal cells treated with BMP9, and partially mediated BMP9-induced acetylcholine production and Chat gene expression. BMP9-induced Ngf gene expression was detected in postmitotic cells, required new protein synthesis and was blocked by BMP type I receptor inhibition. Cholinergic neurons were isolated by fluorescence-activated cell sorting based on either transgenic expression of green fluorescent protein driven by the Chat promoter or NGF receptor (p75) immunostaining. Although both noncholinergic and cholinergic neurons in untreated cultures expressed similar low levels of Ngf, increased Ngf gene expression was restricted to Chat-positive neurons in BMP9-treated cultures. Likewise, similar levels of Ngf mRNA were detected in p75-negative and p75-positive septal cells, yet only p75-positive BFCN increased their Ngf gene expression when treated with BMP9, and only these cells expressed the Alk1 BMP receptor. The data suggest an autocrine/paracrine role for NGF in the development and/or maintenance of BFCN and imply that the stimulation of NGF production and release contributes to the cholinergic-supportive properties of BMP9.


Assuntos
Acetilcolina/metabolismo , Fator 2 de Diferenciação de Crescimento/farmacologia , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Septo do Cérebro/citologia , Septo do Cérebro/embriologia , Fatores Etários , Análise de Variância , Animais , Células Cultivadas , Colina O-Acetiltransferase/genética , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Citometria de Fluxo/métodos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Fluorescência Verde/genética , Camundongos , Camundongos Transgênicos , Fatores de Crescimento Neural/genética , Gravidez , RNA Mensageiro/metabolismo , Receptor de Fator de Crescimento Neural/metabolismo
14.
J Biol Chem ; 284(4): 1982-9, 2009 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-19001366

RESUMO

Choline is an essential nutrient that, via its metabolite betaine, serves as a donor of methyl groups used in fetal development to establish the epigenetic DNA and histone methylation patterns. Supplementation with choline during embryonic days (E) 11-17 in rats improves memory performance in adulthood and protects against age-related memory decline, whereas choline deficiency impairs certain cognitive functions. We previously reported that global and gene-specific DNA methylation increased in choline-deficient fetal brain and liver, and these changes in DNA methylation correlated with an apparently compensatory up-regulation of the expression of DNA methyltransferase Dnmt1. In the current study, pregnant rats were fed a diet containing varying amounts of choline (mmol/kg: 0 (deficient), 8 (control), or 36 (supplemented)) during E11-17, and indices of histone methylation were assessed in liver and frontal cortex on E17. The mRNA and protein expression of histone methyltransferases G9a and Suv39h1 were directly related to the availability of choline. DNA methylation of the G9a and Suv39h1 genes was up-regulated by choline deficiency, suggesting that the expression of these enzymes is under negative control by methylation of their genes. The levels of H3K9Me2 and H3K27Me3, tags of transcriptionally repressed chromatin, were up-regulated by choline supplementation, whereas the levels of H3K4Me2, associated with active promoters, were highest in choline-deficient rats. These data show that maternal choline supply during pregnancy modifies fetal histone and DNA methylation, suggesting that a concerted epigenomic mechanism contributes to the long term developmental effects of varied choline intake in utero.


Assuntos
Encéfalo/metabolismo , Colina/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Fígado/metabolismo , Metiltransferases/metabolismo , Gravidez/metabolismo , Proteínas Repressoras/metabolismo , Animais , Encéfalo/embriologia , Ilhas de CpG/genética , Feminino , Feto/embriologia , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Fígado/embriologia , Metilação , Metiltransferases/genética , Gravidez/genética , Regiões Promotoras Genéticas/genética , Ratos , Proteínas Repressoras/genética
15.
FASEB J ; 23(4): 1054-63, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19047067

RESUMO

Choline is an essential nutrient that serves as a donor of metabolic methyl groups used during gestation to establish the epigenetic DNA methylation patterns that modulate tissue-specific gene expression. Because the mammary gland begins its development prenatally, we hypothesized that choline availability in utero may affect the gland's susceptibility to cancer. During gestational days 11-17, pregnant rats were fed a control, choline-supplemented, or choline-deficient diet (8, 36, and 0 mmol/kg of choline, respectively). On postnatal day 65, the female offspring received 25 mg/kg of a carcinogen 7,12-dimethylbenz[alpha]anthracene. Approximately 70% of the rats developed mammary adenocarcinomas; prenatal diet did not affect tumor latency, incidence, size, and multiplicity. Tumor growth rate was inversely related to choline content in the prenatal diet, resulting in 50% longer survival until euthanasia, determined by tumor size, of the prenatally choline-supplemented rats compared with the prenatally choline-deficient rats. This was accompanied by distinct expression patterns of approximately 70 genes in tumors derived from the three dietary groups. Tumors from the prenatally choline-supplemented rats overexpressed genes that confer favorable prognosis in human cancers (Klf6, Klf9, Nid2, Ntn4, Per1, and Txnip) and underexpressed those associated with aggressive disease (Bcar3, Cldn12, Csf1, Jag1, Lgals3, Lypd3, Nme1, Ptges2, Ptgs1, and Smarcb1). DNA methylation within the tumor suppressor gene, stratifin (Sfn, 14-3-3sigma), was proportional to the prenatal choline supply and correlated inversely with the expression of its mRNA and protein in tumors, suggesting that an epigenetic mechanism may underlie the altered molecular phenotype and tumor growth. Our results suggest a role for adequate maternal choline nutrition during pregnancy in prevention/alleviation of breast cancer in daughters.


Assuntos
9,10-Dimetil-1,2-benzantraceno/metabolismo , Carcinógenos/metabolismo , Colina/metabolismo , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/metabolismo , Adenocarcinoma/induzido quimicamente , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Deficiência de Colina/metabolismo , Análise por Conglomerados , Feminino , Feto/embriologia , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Imuno-Histoquímica , Neoplasias Mamárias Experimentais/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida , Fatores de Tempo
16.
Brain Res ; 1237: 84-90, 2008 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-18778692

RESUMO

Adequate choline levels in rodents during gestation have been shown to be critical to several functions, including certain learning and memory functions, when tested at adulthood. Choline is a selective agonist for the alpha7 nicotinic receptor which appears in development before acetylcholine is present. Normal sensory inhibition is dependent, in part, upon sufficient numbers of this receptor in the hippocampus. The present study assessed sensory inhibition in Sprague-Dawley rats gestated on normal (1.1 g/kg), deficient (0 g/kg) or supplemented (5 g/kg) choline in the maternal diet during the critical period for cholinergic cell development (E12-18). Rats gestated on deficient choline showed abnormal sensory inhibition when tested at adulthood, while rats gestated on normal or supplemented choline showed normal sensory inhibition. Assessment of hippocampal alpha-bungarotoxin to visualize nicotinic alpha7 receptors revealed no difference between the gestational choline levels. These data suggest that attention to maternal choline levels for human pregnancy may be important to the normal functioning of the offspring.


Assuntos
Deficiência de Colina/fisiopatologia , Colina/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Estimulação Acústica/métodos , Animais , Animais Recém-Nascidos , Bungarotoxinas/metabolismo , Colina/administração & dosagem , Deficiência de Colina/induzido quimicamente , Deficiência de Colina/patologia , Potenciais Evocados Auditivos/efeitos dos fármacos , Potenciais Evocados Auditivos/fisiologia , Feminino , Hipocampo/metabolismo , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Tempo de Reação , Reflexo de Sobressalto/fisiologia
17.
Brain Res ; 1237: 101-9, 2008 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-18778693

RESUMO

Nutritional status during pregnancy and lactation can influence behavioral and anatomical characteristics of several neurological disorders in the offspring, including Rett syndrome (RTT). RTT is associated with mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCp2), a transcriptional repressor that binds methylated DNA. In Mecp2(1lox) mice, a model of RTT, enhancing maternal nutrition through choline supplementation attenuates motor coordination deficits in the mutant offspring. Here, we examine alterations in brain volume and growth factor expression in the cerebellum and striatum, motor regions that may contribute to the improved behavioral performance seen with choline supplementation. Mecp2(1lox) dams were given choline in drinking water, and pups nursed from birth to weaning. Brains of male offspring were collected at postnatal day 42 for volumetric and growth factor expression analyses. Compared to wild-type mice, Mecp2(1lox) null mice had decreased whole brain, cerebellar and striatal volume. Choline supplementation had no effect on brain volume. Nerve growth factor and insulin-like growth factor-1 expression was similar between wild-type and Mecp2(1lox) mice while brain derived neurotrophic factor was reduced in Mecp2(1lox) mice. Choline supplementation increased striatal nerve growth factor expression in wild-type and Mecp2(1lox) mice, suggesting that neuronal proliferation and survival may contribute to improved motor performance in this model of RTT.


Assuntos
Encéfalo/patologia , Colina/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Crescimento Neural/metabolismo , Nootrópicos/administração & dosagem , Síndrome de Rett , Animais , Animais Recém-Nascidos , Comportamento Animal , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática/métodos , Regulação da Expressão Gênica/genética , Masculino , Proteína 2 de Ligação a Metil-CpG/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Rett/dietoterapia , Síndrome de Rett/genética , Síndrome de Rett/patologia
18.
Brain Res ; 1237: 153-66, 2008 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-18778697

RESUMO

Altered dietary choline availability early in life leads to persistent changes in spatial memory and hippocampal plasticity in adulthood. Developmental programming by early choline nutrition may determine the range of adult choline intake that is optimal for the types of neural plasticity involved in cognitive function. To test this, male Sprague-Dawley rats were exposed to a choline chloride deficient (DEF), sufficient (CON), or supplemented (SUP) diet during embryonic days 12-17 and then returned to a control diet (1.1 g choline chloride/kg). At 70 days of age, we found that DEF and SUP rats required fewer choices to locate 8 baited arms of a 12-arm radial maze than CON rats. When switched to a choline-deficient diet (0 g/kg), SUP rats showed impaired performance while CON and DEF rats were unaffected. In contrast, when switched to a choline-supplemented diet (5.0 g/kg), DEF rats' performance was significantly impaired while CON and SUP rats were less affected. These changes in performance were reversible when the rats were switched back to a control diet. In a second experiment, DEF, CON, and SUP rats were either maintained on a control diet, or the choline-supplemented diet. After 12 weeks, DEF rats were significantly impaired by choline supplementation on a matching-to-place water-maze task, which was also accompanied by a decrease in dentate cell proliferation in DEF rats only. IGF-1 levels were elevated by both prenatal and adult choline supplementation. Taken together, these findings suggest that the in utero availability of an essential nutrient, choline, causes differential behavioral and neuroplastic sensitivity to the adult choline supply.


Assuntos
Colina/administração & dosagem , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Nootrópicos/administração & dosagem , Fenômenos Fisiológicos da Nutrição Pré-Natal , Animais , Comportamento Animal , Bromodesoxiuridina/metabolismo , Proliferação de Células/efeitos dos fármacos , Deficiência de Colina/patologia , Deficiência de Colina/fisiopatologia , Suplementos Nutricionais , Feminino , Hipocampo/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Gravidez , Ratos , Ratos Sprague-Dawley , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologia
19.
Brain Res ; 1237: 110-23, 2008 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-18786518

RESUMO

Supplemental choline in the maternal diet produces a lasting enhancement in memory in offspring that resists age-related decline and is accompanied by neuroanatomical, neurophysiological and neurochemical changes in the hippocampus. The present study was designed to examine: 1) if prenatal choline supplementation alters behaviors that contribute to risk or resilience in cognitive aging, and 2) whether, at old age (25 months), prenatally choline-supplemented rats show evidence of preserved hippocampal plasticity. A longitudinal design was used to look at exploration of an open field, with and without objects, at 1 and 24 months of age in male and female rats whose mothers were fed a diet supplemented with choline (SUP; 5 mg/kg choline chloride) or not supplemented (CON; 1.1 mg/kg choline chloride) on embryonic days 12-17. Aging caused a significant decline in open field exploration that was more pronounced in males but interest in novel objects was maintained in both sexes. Prenatal choline supplementation attenuated, but did not prevent age-related decline in exploration in males and increased object exploration in young females. Following behavioral assessment, rats were euthanized to assess markers of hippocampal plasticity. Aged SUP males and females had more newly proliferated cells in the hippocampal dentate gyrus and protein levels of vascular endothelial growth factor (VEGF) and neurotrophin-3 (NT-3) were significantly elevated in female SUP rats in comparison to all other groups. Taken together, these findings provide the first evidence that prenatal choline supplementation causes changes in exploratory behaviors over the lifespan and preserves some features of hippocampal plasticity that can be seen even at 2 years of age.


Assuntos
Colina/administração & dosagem , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Nootrópicos/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Comportamento Animal , Bromodesoxiuridina/metabolismo , Proliferação de Células , Corticosterona/farmacologia , Comportamento Exploratório/fisiologia , Feminino , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto , Plasticidade Neuronal/fisiologia , Gravidez , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Estresse Psicológico/tratamento farmacológico
20.
Brain Res ; 1237: 124-35, 2008 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-18786520

RESUMO

Choline is an essential nutrient whose availability during the second half of gestation produces long-lasting cognitive effects. Rats that obtain supplemental choline during embryonic day (E) 11-17 have enhanced depolarization-evoked acetylcholine (ACh) release from hippocampal slices, whereas choline deficiency during this time reduces this release. Previously we reported that rats whose mothers consumed a choline-supplemented diet during E11-17 have higher levels of insulin-like growth factor II (IGF2) mRNA and protein in the frontal cortex compared to control and prenatally choline-deficient animals. Since IGF2 has been shown to stimulate endogenous ACh release, we measured the release of ACh from hippocampal and frontal cortical slices from rats on postnatal day (P) 18, P24, P34 and P80 in response to a depolarizing concentration of potassium (45 mM or 25 mM) or to IGF2 treatment in the absence or presence of a depolarizing concentration of potassium (25 mM). On P18, IGF2/depolarization-evoked ACh release from hippocampal slices was enhanced by prenatal choline supplementation. In the frontal cortex on P80, prenatal choline supplementation dramatically potentiated ACh release induced by depolarization, IGF2 or the combination of the two. On P18 and P90 and in both brain regions, IGF2 mRNA and protein levels, as well as protein levels of the IGF2 receptor (IGF2R), were higher in prenatally choline-supplemented rats. Choline supplementation also increased IGF2R mRNA levels in the septum. In summary, prenatal choline supplementation produced alterations in IGF2 signaling, via increased levels of IGF2 and IGF2R, which may enhance cholinergic neurotransmission and confer neuroprotection against insult.


Assuntos
Acetilcolina/metabolismo , Colina , Lobo Frontal/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipocampo/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Receptor IGF Tipo 2/metabolismo , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Fator de Crescimento Insulin-Like II/genética , Masculino , Gravidez , Ratos , Receptor IGF Tipo 2/genética
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