INSERM, U836, BP 170, and Université Joseph Fourier, Grenoble Institut des Neurosciences, BP 170, Grenoble Cedex 9, F-38042, France.
J Neurosci. 2014 Apr 23;34(17):6084-97. doi: 10.1523/JNEUROSCI.4261-13.2014.
Tau is a microtubule-associated protein well known for its stabilization of microtubules in axons. Recently, it has emerged that tau participates in synaptic function as part of the molecular pathway leading to amyloid-beta (Aβ)-driven synaptotoxicity in the context of Alzheimer's disease. Here, we report the implication of tau in the profound functional synaptic modification associated with synaptic plasticity. By exposing murine cultured cortical neurons to a pharmacological synaptic activation, we induced translocation of endogenous tau from the dendritic to the postsynaptic compartment. We observed similar tau translocation to the postsynaptic fraction in acute hippocampal slices subjected to long-term potentiation. When we performed live confocal microscopy on cortical neurons transfected with human-tau-GFP, we visualized an activity-dependent accumulation of tau in the postsynaptic density. Coprecipitation using phalloidin revealed that tau interacts with the most predominant cytoskeletal component present, filamentous actin. Finally, when we exposed cortical cultures to 100 nm human synthetic Aβ oligomers (Aβo's) for 15 min, we induced mislocalization of tau into the spines under resting conditions and abrogated subsequent activity-dependent synaptic tau translocation. These changes in synaptic tau dynamics may rely on a difference between physiological and pathological phosphorylation of tau. Together, these results suggest that intense synaptic activity drives tau to the postsynaptic density of excitatory synapses and that Aβo-driven tau translocation to the spine deserves further investigation as a key event toward synaptotoxicity in neurodegenerative diseases.
tau 是一种微管相关蛋白，以稳定轴突中的微管而闻名。最近，tau 作为导致阿尔茨海默病中淀粉样β（Aβ）驱动的突触毒性的分子途径的一部分，参与突触功能已初见端倪。在这里，我们报告了 tau 与突触可塑性相关的深刻功能突触修饰的关联。通过使鼠培养的皮质神经元暴露于药理学突触激活下，我们诱导内源性 tau 从树突向突触后隔室易位。我们在经历长时程增强的急性海马切片中观察到类似的 tau 向突触后部分的易位。当我们对转染人 tau-GFP 的皮质神经元进行活细胞共焦显微镜检查时，我们观察到 tau 在突触后密度中的活性依赖性积累。使用鬼笔环肽进行共沉淀表明 tau 与存在的最主要的细胞骨架成分丝状肌动蛋白相互作用。最后，当我们将皮质培养物暴露于 100nm 人合成 Aβ 寡聚物（Aβo's）15 分钟时，我们在静息状态下诱导 tau 错误定位到棘突中，并消除了随后的活性依赖性突触 tau 易位。这些突触 tau 动力学的变化可能依赖于 tau 的生理和病理磷酸化之间的差异。总之，这些结果表明强烈的突触活动将 tau 驱动到兴奋性突触的突触后密度，并且 Aβo 驱动的 tau 向棘突的易位值得进一步研究，因为它是神经退行性疾病中突触毒性的关键事件。
