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: 7362953
• 负责人: BARBARA J STRUPP
• 金额: $ 62.39万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/7362953
• 关键词: A Mouse; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease risk; Animals; Attention; Basal Nucleus of Meynert; Behavioral; Brain; Brain-Derived Neurotrophic Factor; Cell Count; Cell Nucleus; Characteristics; Choline; Cholinergic Agents; Cognitive; Data; Development; Diet; Dietary intake; Discrimination; Disease; Down Syndrome; Exhibits; Family; Fiber; Functional disorder; Hippocampus (Brain); Immunoblotting; Impaired cognition; Impairment; Individual; Intake; Lactation; Lead; Lesion; Life; Liver; Measures; Medial; Medial Septal Nucleus; Mediating; Memory; Mental Retardation; Mus; NGFR Protein; Nerve Growth Factor Receptors; Nerve Growth Factors; Neurologic; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; Numbers; Pattern; Performance; Perinatal; Population; Pregnancy; Rattus; Recommendation; Research; Rodent; Septal Nuclei; Series; Structure-Activity Relationship; Supplementation; System; Task Performances; Techniques; Testing; Time; Transcriptional Activation; TrkA protein; Up-Regulation; Visual attention; Western Blotting; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; cholinergic neuron; cognitive function; design; frontal lobe; improved; indexing; morphometry; mouse Ts65Dn; mouse model; neuromechanism; neurotrophic factor; postnatal; prevent; receptor; relating to nervous system; septohippocampal; size

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.

描述（由申请人提供）：除了智力低下，患有唐氏综合症（DS）的人普遍发展了成年早期阿尔茨海默氏病（AD）的神经病理学标志。 DS和AD的小鼠模型TS65DN小鼠表现出这些疾病的关键特征，包括胆碱能基础前脑（CBF）神经元的早期变性和认知功能的损害，取决于这些神经元及其投影系统，即表明记忆和注意力功能。我们最近完成了一项研究，以检验以下假设：在怀孕期间和泌乳过程中补充过量胆碱的孕产妇饮食会减少TS65DN小鼠中观察到的注意力障碍。这项研究揭示了TS65DN小鼠补充围产期胆碱的显着益处：它们在一系列视觉注意任务上的表现明显优于未补充的TS65DN小鼠，实际上，在某些任务上，它们与失眠（2N）控件没有差异。对于一项任务，2N小鼠还受益于增加的母体胆碱摄入量。本文提出的研究旨在详细阐述这些观察结果，该观察结果有三个特定的目的：（1）检验以下假设：围产期胆碱补充物在TS65DN和2N小鼠中的益处扩展到取决于胆碱能隔膜隔离的功能； （2）为了检验以下假设：TS65DN和2N小鼠中早期补充胆碱产生的认知益处是由胆碱能神经元在特定基础前脑核中的数量，大小和/或表型表达的增加介导的，并且使用不缩写的核心概述了胆碱能力核（内膜核和/核基底）和/或或其核对词。定量形态测定法将与这些动物的记忆和注意力的度量相关，以评估观察到的任何变化的功能意义； （3）为了测试以下假设：TS65DN和2N小鼠的认知功能改善的是通过神经生长因子（NGF）家族的神经营养蛋白及其同源受体在CBF靶区域（额叶皮层和Hippocampus）的变化介导的。这些神经营养蛋白和受体的水平将通过免疫印迹进行测量，并与这些相同受试者的记忆和注意力的度量相关，以建立结构功能关系。在正常啮齿动物中补充围产期胆碱的终身认知和神经益处的证据，而这种DS/AD的小鼠模型增加了可能需要重新评估胆碱摄入量的建议，并且可能需要重新评估胆碱的建议，并且可能需要更高的水平才能获得最佳脑功能。这些最近的发现表明，补充围产期胆碱可能会大大降低DS中看到的认知功能障碍，并降低广泛人口的AD风险和与年龄相关的认知能力下降。拟议的研究旨在增加我们对这些影响的理解，并开始阐明这些行为变化的基本神经机制，这些信息是为了告知这些潜在的胆碱摄入量建议，妊娠，泌乳和早期发育所需的信息。 项目叙述：我们实验室的最新发现表明，在早期发育过程中提供过量的胆碱可能会大大降低唐氏综合症中观察到的认知功能障碍，并降低AD和年龄相关的认知能力下降。拟议的研究旨在增加我们对这些影响的理解，并开始阐明潜在的神经机制。需要此信息来告知您在怀孕期间推荐的胆碱饮食摄入，泌乳和早期产后发育的潜在变化，这可能会导致DS和总体人群的认知功能终生改善。