Department for Translational Brain Research, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Munich Cluster of Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich, Munich, Germany.
Brain. 2019 Apr 1;142(4):1051-1062. doi: 10.1093/brain/awz035.
Pathological alterations of tau protein play a significant role in the emergence and progression of neurodegenerative disorders. Tauopathies are characterized by detachment of the tau protein from neuronal microtubules, and its subsequent aberrant hyperphosphorylation, aggregation and cellular distribution. The exact nature of tau protein species causing neuronal malfunction and degeneration is still unknown. In the present study, we used mice transgenic for human tau with the frontotemporal dementia with parkinsonism-associated P301S mutation. These mice are prone to develop fibrillar tau inclusions, especially in the spinal cord and brainstem. At the same time, cortical neurons are not as strongly affected by fibrillar tau forms, but rather by soluble tau forms. We took advantage of the possibility to induce formation of neurofibrillary tangles in a subset of these cortical neurons by local injection of preformed synthetic tau fibrils. By using chronic in vivo two-photon calcium imaging in awake mice, we were able for the first time to follow the activity of individual tangle-bearing neurons and compare it to the activity of tangle-free neurons over the disease course. Our results revealed strong reduction of calcium transient frequency in layer 2/3 cortical neurons of P301S mice, independent of neurofibrillary tangle presence. These results clearly point to the impairing role of soluble, mutated tau protein species present in the majority of the neurons investigated in this study.
tau 蛋白的病理性改变在神经退行性疾病的发生和进展中起着重要作用。tau 病的特征是 tau 蛋白从神经元微管上脱离，随后异常过度磷酸化、聚集和细胞分布。导致神经元功能障碍和退化的确切 tau 蛋白种类仍然未知。在本研究中，我们使用了携有人 P301S 突变的额颞叶痴呆相关突变的人 tau 转基因小鼠。这些小鼠易于在脊髓和脑干中形成纤维状 tau 包涵体。同时，皮质神经元受纤维状 tau 形式的影响不如可溶性 tau 形式强。我们利用在这些皮质神经元的一部分中局部注射预先形成的合成 tau 原纤维来诱导神经原纤维缠结形成的可能性。通过在清醒小鼠中进行慢性体内双光子钙成像，我们首次能够跟踪携带神经原纤维缠结的单个神经元的活动，并将其与无缠结神经元在疾病过程中的活动进行比较。我们的结果表明，P301S 小鼠的 2/3 层皮质神经元的钙瞬变频率明显降低，与神经原纤维缠结的存在无关。这些结果清楚地表明，在本研究中研究的大多数神经元中存在的可溶性突变 tau 蛋白种类具有损害作用。
