Morphologic Alterations Associated withTauopothy

本研究的目的是在一种新的人类tau病理模型(hTau小鼠)中确定致病性tau蓄积对突触结构和功能的影响。使用新开发的膜标记技术在固定的脑片上显示海马和皮质突触，我们将确定在tau病理的不同阶段脊椎密度、树突的长度和直径以及突触前终末的数量的变化。我们还将揭示tau异常聚集的最初影响是在突触前还是突触后结构上，以及这种影响是细胞类型和区域特异性的，为了更好地了解与tau病理相关的突触变化的时间尺度，我们将使用经颅双光子成像技术跟踪相同的荧光标记突触。 在存活的hTau小鼠中延长时间(几天到几个月)。与活体成像相结合 方法，系列电子显微镜将被用来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，我们将确定急性脑片中树突干和脊椎的钙动力学是否发生变化，以及树突功能的中断是否发生在任何结构变化之前。总之，这些研究将以前所未有的高空间和时间分辨率为我们提供关于tau病理小鼠模型中突触功能障碍的丰富信息。由于突触功能障碍和病理性tau积聚是阿尔茨海默病(AD)的两个显著特征，因此确定这两个成分之间的关系和突触丢失的细胞机制可能对理解AD的发病机制和 用于开发新的治疗方法。

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.