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

描述（由申请人提供）：除了精神发育迟滞外，唐氏综合征（DS）患者在成年早期普遍出现阿尔茨海默病（AD）的神经病理学特征。DS和AD的小鼠模型Ts 65 Dn小鼠表现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（即外显记忆和注意力功能）的损伤。我们最近完成了一项研究，以测试这一假设，即在怀孕和哺乳期间补充过量胆碱的母体饮食会减轻Ts 65 Dn小鼠的注意力功能障碍。这项研究揭示了围产期胆碱补充对Ts 65 Dn小鼠的显着益处：它们在一系列视觉注意力任务上的表现明显优于未补充的Ts 65 Dn小鼠，事实上，在某些任务上，与双体（2N）对照组没有差异。对于一项任务，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Ts 65 Dn和2N小鼠围产期补充胆碱的益处延伸到依赖于胆碱能隔-海马系统的功能的假设;（2）为了检验早期胆碱补充对Ts 65 Dn和2N小鼠的认知益处是由增加的数量介导的假设，大小和/或胆碱能神经元在特定基底前脑核（内侧隔核和基底核）和/或其投射系统中的表型表达。将定量形态测量与来自这些相同动物的记忆和注意力的测量相关联，以评估任何观察到的变化的功能意义;（3）检验以下假设：Ts 65 Dn和2N小鼠中的认知功能改善是由CBF靶区域（额叶皮质和海马）中神经营养蛋白的神经生长因子（NGF）家族及其同源受体的改变介导的。将使用免疫印迹法测量这些神经营养因子和受体的水平，并将其与来自这些相同受试者的记忆和注意力的测量相关联，以建立结构-功能关系。在正常啮齿动物和DS/AD小鼠模型中，围产期胆碱补充剂对终身认知和神经有益的证据提出了一种可能性，即目前基于预防肝损伤的胆碱摄入量建议可能需要重新评估，并且可能需要更高的水平以实现最佳的脑功能。这些最新的研究结果表明，围产期胆碱补充剂可能会显着降低DS中看到的认知功能障碍，以及降低AD和年龄相关的认知能力下降的风险，在整个人口。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潜在神经机制，这些信息是必要的，以告知这些潜在的变化，建议在怀孕期间，哺乳期和早期发育的胆碱摄入量。

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.