Perinatal choline therapy in a mouse model of Down Syndrome & Alzheimer's Disease
唐氏综合症小鼠模型的围产期胆碱治疗
基本信息
- 批准号:7362953
- 负责人:
- 金额:$ 62.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-02-15 至 2013-01-31
- 项目状态:已结题
- 来源:
- 关键词:A MouseAge-associated memory impairmentAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAnimalsAttentionBasal Nucleus of MeynertBehavioralBrainBrain-Derived Neurotrophic FactorCell CountCell NucleusCharacteristicsCholineCholinergic AgentsCognitiveDataDevelopmentDietDietary intakeDiscriminationDiseaseDown SyndromeExhibitsFamilyFiberFunctional disorderHippocampus (Brain)ImmunoblottingImpaired cognitionImpairmentIndividualIntakeLactationLeadLesionLifeLiverMeasuresMedialMedial Septal NucleusMediatingMemoryMental RetardationMusNGFR ProteinNerve Growth Factor ReceptorsNerve Growth FactorsNeurologicNeuronsNeurotrophic Tyrosine Kinase Receptor Type 1NumbersPatternPerformancePerinatalPopulationPregnancyRattusRecommendationResearchRodentSeptal NucleiSeriesStructure-Activity RelationshipSupplementationSystemTask PerformancesTechniquesTestingTimeTranscriptional ActivationTrkA proteinUp-RegulationVisual attentionWestern Blottingbasal forebrainbasal forebrain cholinergic neuronsbasecholinergiccholinergic neuroncognitive functiondesignfrontal lobeimprovedindexingmorphometrymouse Ts65Dnmouse modelneuromechanismneurotrophic factorpostnatalpreventreceptorrelating to nervous systemseptohippocampalsize
项目摘要
DESCRIPTION (provided by applicant): In addition to mental retardation, individuals with Down syndrome (DS) universally develop the neuropathological hallmarks of Alzheimer's Disease (AD) in early adulthood. A mouse model of DS and AD, the Ts65Dn mouse, exhibits key features of these disorders, including early degeneration of cholinergic basal forebrain (CBF) neurons and impairments in the cognitive functions dependent on these neurons and their projection systems, namely, explicit memory and attentional function. We recently completed a study to test the hypothesis that supplementation of the maternal diet with excess choline during pregnancy and lactation would lessen the attentional dysfunction seen in Ts65Dn mice. This study revealed a remarkable benefit of perinatal choline supplementation for the Ts65Dn mice: They performed significantly better than unsupplemented Ts65Dn mice on a series of visual attention tasks, and in fact, on some tasks, did not differ from the disomic (2N) controls. For one task, the 2N mice also benefited from the increased maternal choline intake. The studies proposed herein are designed to elaborate upon these observations with three Specific Aims: (1) To test the hypothesis that the benefit of perinatal choline supplementation in Ts65Dn and 2N mice extends to functions dependent on the cholinergic septo-hippocampal system; (2) To test the hypothesis that the cognitive benefit produced by early choline supplementation in Ts65Dn and 2N mice is mediated by increased number, size, and/or phenotypic expression of cholinergic neurons in specific basal forebrain nuclei (medial septal nucleus and nucleus basalis) and/or their projection systems, using unbiased stereologic cell counting techniques. Quantitative morphometry will be correlated with measures of memory and attention from these same animals to assess the functional significance of any observed changes; (3) To test the hypothesis that improved cognitive functioning in Ts65Dn and 2N mice is mediated by alterations in the nerve growth factor (NGF) family of neurotrophins and its cognate receptors in CBF target regions (frontal cortex and hippocampus). Levels of these neurotrophins and receptors will be measured using immunoblotting and correlated with measures of memory and attention from these same subjects to establish structure-function relationships. The evidence for lifelong cognitive and neural benefits of perinatal choline supplementation in normal rodents and this mouse model of DS/AD raises the possibility that recommendations for choline intake, currently based on preventing liver damage, may need to be re-evaluated, and that higher levels may be needed for optimal brain function. These recent findings suggest that perinatal choline supplementation might significantly reduce the cognitive dysfunction seen in DS as well as reduce the risk of AD and age-related cognitive decline in the population at large. The proposed research is designed to increase our understanding of these effects and begin to elucidate the underlying neural mechanisms subserving these behavioral changes, information that is needed to inform these potential changes in recommendations for choline intake during pregnancy, lactation, and early development. Project Narrative: Recent findings from our lab suggest that providing excess choline during early development might significantly reduce the cognitive dysfunction seen in Down syndrome and reduce the risk of AD and age-related cognitive decline in the population at large. The proposed research is designed to increase our understanding of these effects and begin to elucidate the underlying neural mechanisms. This information is needed to inform potential changes in the recommended dietary intake of choline during pregnancy, lactation and early postnatal development, which may in turn, lead to lifelong improvements in cognitive functioning for individuals with DS and the population at large.
DESCRIPTION (provided by applicant): In addition to mental retardation, individuals with Down syndrome (DS) universally develop the neuropathological hallmarks of Alzheimer's Disease (AD) in early adulthood. A mouse model of DS and AD, the Ts65Dn mouse, exhibits key features of these disorders, including early degeneration of cholinergic basal forebrain (CBF) neurons and impairments in the cognitive functions dependent on these neurons and their projection systems, namely, explicit memory and attentional function. We recently completed a study to test the hypothesis that supplementation of the maternal diet with excess choline during pregnancy and lactation would lessen the attentional dysfunction seen in Ts65Dn mice. This study revealed a remarkable benefit of perinatal choline supplementation for the Ts65Dn mice: They performed significantly better than unsupplemented Ts65Dn mice on a series of visual attention tasks, and in fact, on some tasks, did not differ from the disomic (2N) controls. For one task, the 2N mice also benefited from the increased maternal choline intake. The studies proposed herein are designed to elaborate upon these observations with three Specific Aims: (1) To test the hypothesis that the benefit of perinatal choline supplementation in Ts65Dn and 2N mice extends to functions dependent on the cholinergic septo-hippocampal system; (2) To test the hypothesis that the cognitive benefit produced by early choline supplementation in Ts65Dn and 2N mice is mediated by increased number, size, and/or phenotypic expression of cholinergic neurons in specific basal forebrain nuclei (medial septal nucleus and nucleus basalis) and/or their projection systems, using unbiased stereologic cell counting techniques. Quantitative morphometry will be correlated with measures of memory and attention from these same animals to assess the functional significance of any observed changes; (3) To test the hypothesis that improved cognitive functioning in Ts65Dn and 2N mice is mediated by alterations in the nerve growth factor (NGF) family of neurotrophins and its cognate receptors in CBF target regions (frontal cortex and hippocampus). Levels of these neurotrophins and receptors will be measured using immunoblotting and correlated with measures of memory and attention from these same subjects to establish structure-function relationships. The evidence for lifelong cognitive and neural benefits of perinatal choline supplementation in normal rodents and this mouse model of DS/AD raises the possibility that recommendations for choline intake, currently based on preventing liver damage, may need to be re-evaluated, and that higher levels may be needed for optimal brain function. These recent findings suggest that perinatal choline supplementation might significantly reduce the cognitive dysfunction seen in DS as well as reduce the risk of AD and age-related cognitive decline in the population at large. The proposed research is designed to increase our understanding of these effects and begin to elucidate the underlying neural mechanisms subserving these behavioral changes, information that is needed to inform these potential changes in recommendations for choline intake during pregnancy, lactation, and early development. Project Narrative: Recent findings from our lab suggest that providing excess choline during early development might significantly reduce the cognitive dysfunction seen in Down syndrome and reduce the risk of AD and age-related cognitive decline in the population at large. The proposed research is designed to increase our understanding of these effects and begin to elucidate the underlying neural mechanisms. This information is needed to inform potential changes in the recommended dietary intake of choline during pregnancy, lactation and early postnatal development, which may in turn, lead to lifelong improvements in cognitive functioning for individuals with DS and the population at large.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('BARBARA J STRUPP', 18)}}的其他基金
Perinatal choline therapy in a mouse model of Down Syndrome & Alzheimer's Disease
唐氏综合症小鼠模型的围产期胆碱治疗
- 批准号:
7760908 - 财政年份:2008
- 资助金额:
$ 62.39万 - 项目类别:
Perinatal choline therapy in a mouse model of Down Syndrome & Alzheimer's Disease
唐氏综合症小鼠模型的围产期胆碱治疗
- 批准号:
8049067 - 财政年份:2008
- 资助金额:
$ 62.39万 - 项目类别:
Perinatal choline therapy in a mouse model of Down Syndrome & Alzheimer's Disease
唐氏综合症小鼠模型的围产期胆碱治疗
- 批准号:
7568186 - 财政年份:2008
- 资助金额:
$ 62.39万 - 项目类别:
Perinatal choline therapy in a mouse model of Down Syndrome & Alzheimer's Disease
唐氏综合症小鼠模型的围产期胆碱治疗
- 批准号:
8211029 - 财政年份:2008
- 资助金额:
$ 62.39万 - 项目类别:
PRENATAL COCAINE EXPOSURE AND ATTENTIONAL DYSFUNCTION
产前接触可卡因和注意力功能障碍
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6858753 - 财政年份:2002
- 资助金额:
$ 62.39万 - 项目类别:
PRENATAL COCAINE EXPOSURE AND ATTENTIONAL DYSFUNCTION
产前接触可卡因和注意力功能障碍
- 批准号:
6711679 - 财政年份:2002
- 资助金额:
$ 62.39万 - 项目类别:
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产前接触可卡因和注意力功能障碍
- 批准号:
6619545 - 财政年份:2002
- 资助金额:
$ 62.39万 - 项目类别:
PRENATAL COCAINE EXPOSURE AND ATTENTIONAL DYSFUNCTION
产前接触可卡因和注意力功能障碍
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