促聚集 Tau 由于结构改变和 Ca(++) 失调而损害苔藓纤维可塑性。

INTRODUCTION

We used an inducible mouse model expressing the Tau repeat domain with the pro-aggregant mutation ΔK280 to analyze presynaptic Tau pathology in the hippocampus.

RESULTS

Expression of pro-aggregant Tau(RDΔ) leads to phosphorylation, aggregation and missorting of Tau in area CA3. To test presynaptic pathophysiology we used electrophysiology in the mossy fiber tract. Synaptic transmission was severely disturbed in pro-aggregant Tau(RDΔ) and Tau-knockout mice. Long-term depression of the mossy fiber tract failed in pro-aggregant Tau(RDΔ) mice. We observed an increase in bouton size, but a decline in numbers and presynaptic markers. Both pre-and postsynaptic structural deficits are preventable by inhibition of Tau(RDΔ) aggregation. Calcium imaging revealed progressive calcium dysregulation in boutons of pro-aggregant Tau(RDΔ) mice. In N2a cells we observed this even in cells without tangle load, whilst in primary hippocampal neurons transient Tau(RDΔ) expression alone caused similar Ca(++) dysregulation. Ultrastructural analysis revealed a severe depletion of synaptic vesicles pool in accordance with synaptic transmission impairments.

CONCLUSIONS

We conclude that oligomer formation by Tau(RDΔ) causes pre- and postsynaptic structural deterioration and Ca(++) dysregulation which leads to synaptic plasticity deficits.

简介

我们使用表达具有促聚集突变 ΔK280 的 Tau 重复结构域的可诱导小鼠模型，来分析海马体中的 Tau 病理。

结果

促聚集 Tau（RDΔ）的表达导致 Tau 在 CA3 区的磷酸化、聚集和错误分拣。为了测试突触前病理生理学，我们在苔藓纤维束中使用电生理学。促聚集 Tau（RDΔ）和 Tau 敲除小鼠的突触传递严重受损。长时程压抑在促聚集 Tau（RDΔ）小鼠中失败。我们观察到棘突大小增加，但棘突数量和突触前标志物减少。Tau（RDΔ）聚集的抑制可预防这两种前和后突触结构缺陷。钙成像显示促聚集 Tau（RDΔ）小鼠棘突中的钙失调呈进行性增加。在 N2a 细胞中，即使在没有缠结负荷的细胞中，我们也观察到了这种情况，而在原代海马神经元中，短暂的 Tau（RDΔ）表达本身就会导致类似的 Ca（++）失调。超微结构分析显示，突触小泡池严重耗竭，与突触传递损伤一致。