Institute of Neuroimmunology, Slovak Academy of Sciences Bratislava, Slovak Republic.
Axon Neuroscience GmbH Bratislava, Slovak Republic ; Institute of Mathematics and Statistics, Masaryk University Brno, Czech Republic.
Front Cell Neurosci. 2015 Feb 23;9:24. doi: 10.3389/fncel.2015.00024. eCollection 2015.
Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer's disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre- and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology.
突触衰竭和神经纤维变性是阿尔茨海默病（AD）认知功能障碍的两个主要神经病理学基础。只有少数研究表明这两个 AD 标志物之间存在直接关系。为了研究 tau 介导的突触损伤，我们使用了在皮质中形成广泛神经纤维病理的 tau 病大鼠模型。通过皮质突触的分段，我们在突触前区发现内源性大鼠 tau 异构体增加，并错误地分类到突触后密度（PSD）。截断的转基因 tau 分布在两个区室中，表现出每个突触区室特有的特定磷酸化模式。在突触前区室中，截断的 tau 与微管的动态稳定性受损有关，这可能是突触小泡减少的原因。在 PSD 中，截断的 tau 降低了神经丝的水平。截断的 tau 还显著降低了突触水平的 Aβ40，但不降低 Aβ42。这些数据表明，截断的 tau 在突触前和突触后区室中差异地上调了突触蛋白质组。重要的是，我们表明 Aβ 的改变可能是截断的 tau 病变的下游结果。
