Morphologic Alterations Associated withTauopothy

与Taupothy相关的形态改变

• 批准号: 6966711
• 负责人: WENBIAO GAN
• 金额: $ 20.99万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966711
• 关键词: Alzheimer' s disease; age difference; bioimaging /biomedical imaging; brain imaging /visualization /scanning; brain morphology; calcium flux; calcium indicator; dendrites; electron microscopy; fluorescent dye /probe; genetically modified animals; laboratory mouse; longitudinal animal study; molecular /cellular imaging; neural degeneration; pathologic process; synapses; tau proteins

The aim of this study is to determine the impact of pathogenic tau accumulation on synaptic structure and function in a new mouse model of human tau pathology (hTau mice). Using a newly developed membrane labeling technique to visualize hippocampal and cortical synapses in fixed brain slices, we will determine changes in spine density, length and diameter of dendrites, and the number of presynaptic terminals at different stages of tau pathology. We will also reveal whether the initial effects of abnormal tau accumulation are on pre- or postsynaptic structures, and whether such effects are cell-type and region specific, In order to better understand the time scale of synaptic changes associated with tau pathology, we will use a transcranial two-photon imaging technique to follow the same fluorescently-labeled synapses over extended periods of time (days to months) in living hTau mice. In combination with in vivo imaging approaches, serial electron microscopy will be used to further explore ultrastructural correlates of synaptic abnormalities. To investigate synaptic dysfunction in hTau mice, we will determine if calcium dynamics are altered in dendritic shafts and spines in acute brain slices, and if the disruption of dendritic functionality occurs prior to any structural alterations. Together, these studies will provide us a wealth of information on synaptic dysfunction in the mouse model of tau pathology at an unprecedented high spatial and temporal resolution. Because synapse dysfunction and pathogenic tau accumulation are two prominent features in Alzheimer's disease (AD), determining the relationship between these two components and cellular mechanisms underlying synapse loss is likely to be important for understanding the pathogenesis of AD and for developing new therapeutic approaches.

这项研究的目的是确定致病性TAU积累对人tau病理学新小鼠模型（HTAU小鼠）中突触结构和功能的影响。使用新开发的膜标记技术可视化固定脑切片中的海马和皮质突触，我们将确定脊柱密度，长度和直径的变化，以及在Tau病理学的不同阶段的突触前终端数量。我们还将揭示异常TAU积累的初始影响是否对突触前结构或突触后结构，以及此类作用是否为细胞类型和特定区域，以便更好地了解与Tau病理相关的突触变化的时间尺度，我们将使用经颅两光子成像技术遵循相同的荧光标记的突触 活着的HTAU小鼠的长时间（天到几个月）。结合体内成像 方法，串行电子显微镜将用于进一步探索突触异常的超微结构相关性。为了研究HTAU小鼠的突触功能障碍，我们将确定在急性脑切片中的树突轴和脊柱中钙动力学是否改变，以及在任何结构变化之前发生树突状功能的破坏。总之，这些研究将为我们提供大量有关tau病理小鼠病理模型的突触功能障碍的信息，这是前所未有的高空间和时间分辨率。因为突触功能障碍和致病性TAU积累是阿尔茨海默氏病（AD）的两个突出特征，因此确定这两个成分与突触损失的细胞机制之间的关系对于理解AD和AD的发病机制可能很重要。 用于开发新的治疗方法。