Tauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer’s patients’ brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer’s disease and other tauopathies.

Tau蛋白病，包括阿尔茨海默病 (AD) 和伴有 Tau 病理学的额颞叶变性 (FTLD-tau)，是一组以 Tau 过度磷酸化为特征的神经退行性疾病。Tau 的翻译后修饰（例如磷酸化和截短）已被证明是这些 tau 病分子发病机制中的重要步骤。在这项工作中，我们使用 qPCR 证明了人类神经母细胞瘤细胞中以及更大程度上人类 RNA 脑样本中内含子 12 保留产生的新的人类特异性 Tau 截短形式的存在，并进一步证实了更大的人类 RNA-seq 样本数据库。通过蛋白质印迹法发现阿尔茨海默病患者大脑中这种新 Tau 亚型的蛋白质水平降低（Braak I n  = 3；Braak II n  = 6，Braak III n  = 3，Braak IV n  = 1，Braak V n  = 10，Braak VI n  = 8）相对于非痴呆对照受试者（n  = 9），表明这种截短亚型的缺乏可能在病理学中发挥重要作用。这种新的 Tau 异构体通过磷酸化和微管结合亲和力表现出类似的转录后修饰，但更有趣的是，它比其他 Tau 异构体更不易聚集。最后，我们提出的证据表明，这种新的 Tau 亚型可能与 GSK3β 的抑制有关，GSK3β 会通过调节富含丝氨酸/精氨酸的剪接因子 2 (SRSF2) 来介导内含子 12 的保留。我们的结果表明存在一种重要的新 Tau 亚型，并表明对这种不易聚集的 Tau 的进一步研究可能有助于开发阿尔茨海默病和其他 tau 病的未来疗法。