Understanding regulation of MAPT splicing is important to the etiology of many nerurodegenerative diseases, including Alzheimer disease (AD) and progressive supranuclear palsy (PSP), in which different tau isoforms accumulate in pathologic inclusions. MAPT, the gene encoding the tau protein, undergoes complex alternative pre-mRNA splicing to generate six isoforms. Tauopathies can be categorized by the presence of tau aggregates containing either 3 (3R) or 4 (4R) microtubule-binding domain repeats (determined by inclusion/exclusion of exon 10), but the role of the N-terminal domain of the protein, determined by inclusion/exclusion of exons 2 and 3 has been less well studied. Using a correlational screen in human brain tissue, we observed coordination of MAPT exons 2 and 10 splicing. Expressions of exon 2 splicing regulators and subsequently exon 2 inclusion are differentially disrupted in PSP and AD brain, resulting in the accumulation of 1N4R isoforms in PSP and 0N isoforms in AD temporal cortex. Furthermore, we identified different N-terminal isoforms of tau present in neurofibrillary tangles, dystrophic neurites and tufted astrocytes, indicating a role for differential N-terminal splicing in the development of disparate tau neuropathologies. We conclude that N-terminal splicing and combinatorial regulation with exon 10 inclusion/exclusion is likely to be important to our understanding of tauopathies.

了解MAPT剪接的调控对于许多神经退行性疾病的病因学非常重要，包括阿尔茨海默病 (AD) 和进行性核上性麻痹 (PSP)，其中不同的 tau 亚型在病理包涵体中积累。MAPT是编码 tau 蛋白的基因，经过复杂的选择性前 mRNA 剪接，生成六种亚型。tau蛋白病可根据含有 3 (3R) 或 4 (4R) 微管结合结构域重复的 tau 聚集体的存在进行分类（通过外显子 10 的包含/排除来确定），但蛋白质 N 末端结构域的作用，通过外显子 2 和 3 的包含/排除来确定的结果尚未得到充分研究。使用人脑组织中的相关筛选，我们观察到MAPT外显子 2 和 10 剪接的协调。外显子 2 剪接调节因子的表达以及随后的外显子 2 包含在 PSP 和 AD 脑中受到差异性破坏，导致 PSP 中 1N4R 同工型积累，AD 颞皮层中 0N 同工型积累。此外，我们还发现了神经原纤维缠结、营养不良的神经突和簇状星形胶质细胞中存在不同的 tau N 端亚型，表明差异性 N 端剪接在不同 tau 神经病理学发展中的作用。我们得出的结论是，N 端剪接和外显子 10 包含/排除的组合调控可能对我们理解 tau蛋白病很重要。