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）：除了智力低下外，患有唐氏综合症（DS）的个体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 小鼠模型 Ts65Dn 小鼠表现出这些疾病的关键特征，包括胆碱能基底前脑 (CBF) 神经元的早期变性以及依赖这些神经元及其投射系统的认知功能受损，即外显记忆和注意力功能。我们最近完成了一项研究，以检验以下假设：在怀孕和哺乳期间在母亲饮食中补充过量胆碱会减轻 Ts65Dn 小鼠的注意力功能障碍。这项研究揭示了围产期补充胆碱对 Ts65Dn 小鼠的显着益处：它们在一系列视觉注意力任务上比未补充胆碱的 Ts65Dn 小鼠表现明显更好，事实上，在某些任务上，与二体 (2N) 对照组没有差异。对于一项任务，2N 小鼠还受益于母体胆碱摄入量的增加。本文提出的研究旨在通过三个具体目标详细阐述这些观察结果：（1）检验 Ts65Dn 和 2N 小鼠围产期胆碱补充的益处扩展到依赖于胆碱能隔海马系统的功能的假设； (2) 使用无偏立体细胞计数技术，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通过特定基底前脑核（内侧间隔核和基底核）和/或其投射系统中胆碱能神经元的数量、大小和/或表型表达增加介导的。定量形态测量将与这些相同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) 检验以下假设：Ts65Dn 和 2N 小鼠认知功能的改善是通过神经营养因子的神经生长因子 (NGF) 家族及其 CBF 目标区域（额叶皮层和海马）的同源受体的改变介导的。这些神经营养素和受体的水平将使用免疫印迹进行测量，并与这些相同受试者的记忆和注意力测量结果相关联，以建立结构-功能关系。围产期补充胆碱对正常啮齿类动物和这种 DS/AD 小鼠模型具有终生认知和神经益处的证据表明，目前基于预防肝损伤的胆碱摄入建议可能需要重新评估，并且可能需要更高的水平才能实现最佳脑功能。这些最新研究结果表明，围产期补充胆碱可能会显着减少 DS 中的认知功能障碍，并降低整个人群患 AD 和与年龄相关的认知能力下降的风险。拟议的研究旨在增加我们对这些影响的理解，并开始阐明促进这些行为变化的潜在神经机制，以及为怀孕、哺乳和早期发育期间胆碱摄入建议的这些潜在变化提供信息所需的信息。 项目叙述：我们实验室的最新研究结果表明，在早期发育过程中提供过量的胆碱可能会显着减少唐氏综合症中的认知功能障碍，并降低整个人群患 AD 和与年龄相关的认知能力下降的风险。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。需要这些信息来告知妊娠期、哺乳期和产后早期发育期间推荐的胆碱膳食摄入量的潜在变化，这反过来可能导致 DS 患者和广大人群认知功能的终生改善。