Perinatal choline therapy in a mouse model of Down Syndrome & Alzheimer's Disease

描述（由申请人提供）：除了智力低下外，唐氏综合症（DS）患者普遍在成年早期出现阿尔茨海默病（AD）的神经病理特征。DS和AD的小鼠模型Ts65Dn小鼠显示出这些疾病的关键特征，包括胆碱能基底前脑（CBF）神经元的早期变性和依赖于这些神经元及其投射系统的认知功能的损伤，即外显记忆和注意功能。我们最近完成了一项研究，以验证在怀孕和哺乳期间补充过量胆碱的母体饮食可以减轻Ts65Dn小鼠的注意功能障碍的假设。这项研究揭示了围产期补充胆碱对Ts65Dn小鼠的显著益处：它们在一系列视觉注意任务上的表现明显优于未补充Ts65Dn的小鼠，事实上，在一些任务上，与二体对照（2N）没有区别。在一项任务中，2N小鼠也受益于母体胆碱摄入量的增加。本文提出的研究旨在详细阐述这些观察结果，有三个具体目的：(1)验证Ts65Dn和2N小鼠围产期胆碱补充的益处延伸到依赖胆碱能隔海马体系统的功能的假设；(2)利用无偏体细胞计数技术，验证Ts65Dn和2N小鼠早期补充胆碱所产生的认知益处是通过增加特定基底前脑核（中隔核和基底核）和/或其投射系统中胆碱能神经元的数量、大小和/或表型表达来介导的。定量形态学测量将与这些动物的记忆和注意力测量相关联，以评估任何观察到的变化的功能意义；(3)验证Ts65Dn和2N小鼠认知功能的改善是通过神经营养因子（NGF）家族及其同源受体在CBF靶区（额叶皮质和海马）的改变介导的。这些神经营养因子和受体的水平将使用免疫印迹法进行测量，并与来自同一受试者的记忆和注意力测量相关联，以建立结构-功能关系。围产期补充胆碱对正常啮齿动物和这种DS/AD小鼠模型的终身认知和神经有益的证据提出了胆碱摄入量建议的可能性，目前基于预防肝损伤，可能需要重新评估，并且可能需要更高水平的胆碱才能达到最佳的脑功能。这些最近的研究结果表明，围产期补充胆碱可能会显著减少退行性痴呆的认知功能障碍，并降低阿尔茨海默病的风险和总体人群中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，并开始阐明支持这些行为变化的潜在神经机制，以及在怀孕、哺乳期和早期发育期间建议胆碱摄入量的潜在变化所需的信息。项目描述：我们实验室最近的研究结果表明，在早期发育期间提供过量的胆碱可能会显著减少唐氏综合症的认知功能障碍，并降低阿尔茨海默病的风险和与年龄相关的认知能力下降。提出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。需要这些信息来了解在怀孕、哺乳和产后早期发育期间推荐的胆碱饮食摄入量的潜在变化，这可能反过来导致DS患者和整个人群的认知功能终身改善。

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.