Effects of neural progenitor cell transplantation in neonatal Ts65Dn mice.

神经祖细胞移植对新生 Ts65Dn 小鼠的影响。

• 批准号: 7408361
• 负责人: Angela Lynn Rachubinski
• 金额: $ 2.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408361
• 关键词: Age; Age-Months; Alzheimer' s Disease; Animals; Area; Behavioral Research; Birth; Brain; Child; Childhood; Chromosomes, Human, Pair 21; Cognition; Cognitive; Cues; Development; Diploid Cells; Diploidy; Disease; Down Syndrome; Early treatment; Face; Golgi Apparatus; Growth Factor; Hippocampus (Brain); Histocytochemistry; Impaired cognition; Implant; Individual; Lead; Learning; Longitudinal Studies; Medial; Mediating; Memory; Mental Retardation; Modeling; Morphology; Mus; Neonatal; Neuroanatomy; Neuroglia; Neurons; Nuclear Pore Complex; Pathology; Pathway interactions; Prefrontal Cortex; Presenile Alzheimer Dementia; Public Health; Staining method; Stains; Stem cell transplant; Stress; Structure; Synaptophysin; Transplantation; Trisomy 16; Work; behavior test; cognitive function; day; density; fetal; migration; mouse Ts65Dn; mouse model; nerve stem cell; postnatal; presynaptic; prevent

DESCRIPTION (provided by applicant): The triplication of chromosome 21 results in mental retardation for children with Down syndrome (DS). Although the brain is somewhat compromised at birth, much of the abnormal development associated with DS occurs in postnatal developing structures, such as the hippocampus. Indeed, children with DS have particular difficulty with hippocampal-mediated spatial tasks. In addition to childhood learning delays, individuals with DS are subjected to the additional cognitive stress of early Alzheimer's disease. Previous work in the fetal lethal Trisomy 16 DS mouse model demonstrated diploid cells in Ts16-diploid chimeric mice prevent the lethality and the chimeric mice survive up to one year. Neural progenitor cells (NPC) have been used to treat diseases with a global pathology, as is seen in DS. NPC can migrate, differentiate into glia and neurons, and secrete growth factors to promote the survival of and provide guidance cues for endogenous neurons. This has lead to the hypothesis that NPC may be useful as a very early treatment of DS and model a more normal neuro-anatomical development during the critical early learning period. The proposed longitudinal study will examine the effects of NPC transplantation on cognition and neuroanatomy in the DS mouse model, the Ts65Dn mouse. Aim 1: Determine if murine NPC (mNPC) transplanted into the hippocampus can alleviate the early and late cognitive dysfunction in Ts65Dn mice. Postnatal day 2 mice will be bilaterally implanted with C17.2 mNPC into the hippocampus. Behavior testing will assess cognitive function at 2, 6, and 12 months of age. Three different behavior tests will be employed to elicit the function of specific components of the learning and memory pathway. Aim 2: Determine the level of mNPC survival and their fate over the lifetime of the transplanted mice. A subset of animals will be analyzed immunohisto- chemically after each round of behavior testing. mNPC survival, migration, and differentiation will be assessed, with higher mNPC concentrations expected in areas involved in learning and memory (the hippocampus, medial septum, and prelimbic prefrontal cortex). Aim 3: Investigate alterations in presynaptic densities and dendritic morphology in the hippocampus and prefrontal cortex. Golgi staining and immuno- histochemistry against synaptophysin will be used to examine dendritic morphology and presynaptic density, respectively. Results from Aims 2 and 3 will be correlated with behavioral research obtained in Aim 1. Public Health Relevance: The use of NPC at an early age may be able to increase cognitive function and make learning easier for children with DS. Furthermore, allowing the brain to make the correct initial connections may prevent the early onset of Alzheimer's disease that people with Down syndrome face.

描述（申请人提供）：21 号染色体三倍体导致唐氏综合症 (DS) 儿童智力低下。尽管大脑在出生时就受到一定程度的损害，但与 DS 相关的大部分异常发育发生在出生后的发育结构中，例如海马体。事实上，患有 DS 的儿童在处理海马介导的空间任务时尤其困难。除了童年学习迟缓之外，患有 DS 的人还遭受早期阿尔茨海默病的额外认知压力。先前对胎儿致死性 16 三体 DS 小鼠模型的研究表明，Ts16-二倍体嵌合小鼠中的二倍体细胞可防止致死性，并且嵌合小鼠可存活长达一年。神经祖细胞 (NPC) 已被用于治疗具有整体病理学的疾病，如 DS 中所见。 NPC可以迁移、分化为胶质细胞和神经元，并分泌生长因子以促进内源性神经元的存活并为内源性神经元提供引导信号。这导致了这样的假设：NPC 可能有助于 DS 的早期治疗，并在关键的早期学习期间模拟更正常的神经解剖学发育。拟议的纵向研究将检查 NPC 移植对 DS 小鼠模型（Ts65Dn 小鼠）认知和神经解剖学的影响。目标 1：确定移植到海马的小鼠 NPC (mNPC) 是否可以缓解 Ts65Dn 小鼠的早期和晚期认知功能障碍。出生后第2天的小鼠将被双侧植入C17.2 mNPC至海马体中。行为测试将评估 2、6 和 12 个月大时的认知功能。将采用三种不同的行为测试来得出学习和记忆途径的特定组成部分的功能。目标 2：确定 mNPC 的存活水平及其在移植小鼠一生中的命运。每轮行为测试后将对一部分动物进行免疫组织化学分析。将评估 mNPC 的存活、迁移和分化，预计参与学习和记忆的区域（海马体、内侧隔膜和前边缘前额叶皮层）的 mNPC 浓度较高。目标 3：研究海马和前额皮质突触前密度和树突形态的变化。高尔基染色和针对突触素的免疫组织化学将分别用于检查树突形态和突触前密度。目标 2 和 3 的结果将与目标 1 中获得的行为研究相关联。 公共健康相关性：早期使用 NPC 可能能够增强 DS 儿童的认知功能并使学习更容易。此外，让大脑建立正确的初始连接可能会预防唐氏综合症患者早期罹患阿尔茨海默病。