Tanz Centre for Research in Neurodegenerative Disease (CRND), University of Toronto, Krembil Discovery Tower, 60 Leonard Ave, Toronto, ON, M5T 0S8, Canada.
Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia.
Acta Neuropathol. 2023 Sep;146(3):395-414. doi: 10.1007/s00401-023-02604-x. Epub 2023 Jun 24.
Microtubule-associated protein tau (MAPT) aggregates in neurons, astrocytes and oligodendrocytes in a number of neurodegenerative diseases, including progressive supranuclear palsy (PSP). Tau is a target of therapy and the strategy includes either the elimination of pathological tau aggregates or reducing MAPT expression, and thus the amount of tau protein made to prevent its aggregation. Disease-associated tau affects brain regions in a sequential manner that includes cell-to-cell spreading. Involvement of glial cells that show tau aggregates is interpreted as glial cells taking up misfolded tau assuming that glial cells do not express enough MAPT. Although studies have evaluated MAPT expression in human brain tissue homogenates, it is not clear whether MAPT expression is compromised in cells accumulating pathological tau. To address these perplexing aspects of disease pathogenesis, this study used RNAscope combined with immunofluorescence (AT8), and single-nuclear(sn) RNAseq to systematically map and quantify MAPT expression dynamics across different cell types and brain regions in controls (n = 3) and evaluated whether tau cytopathology affects MAPT expression in PSP (n = 3). MAPT transcripts were detected in neurons, astrocytes and oligodendrocytes, and varied between brain regions and within each cell type, and were preserved in all cell types with tau aggregates in PSP. These results propose a complex scenario in all cell types, where, in addition to the ingested misfolded tau, the preserved cellular MAPT expression provides a pool for local protein production that can (1) be phosphorylated and aggregated, or (2) feed the seeding of ingested misfolded tau by providing physiological tau, both accentuating the pathological process. Since tau cytopathology does not compromise MAPT gene expression in PSP, a complete loss of tau protein expression as an early pathogenic component is less likely. These observations provide rationale for a dual approach to therapy by decreasing cellular MAPT expression and targeting removal of misfolded tau.
微管相关蛋白 tau（MAPT）在神经元、星形胶质细胞和少突胶质细胞中聚集，这是许多神经退行性疾病的特征，包括进行性核上性麻痹（PSP）。tau 是治疗的靶点，策略包括消除病理性 tau 聚集体或降低 MAPT 表达，从而减少 tau 蛋白的产生以防止其聚集。与疾病相关的 tau 以一种顺序的方式影响大脑区域，包括细胞间传播。tau 聚集体出现在星形胶质细胞中被解释为星形胶质细胞摄取错误折叠的 tau，假设星形胶质细胞不表达足够的 MAPT。尽管已经评估了人类脑组织匀浆中的 MAPT 表达，但尚不清楚在积累病理性 tau 的细胞中 MAPT 表达是否受损。为了解决疾病发病机制中这些令人困惑的方面，本研究使用 RNAscope 结合免疫荧光（AT8）和单核 RNAseq 系统地绘制和量化了对照（n=3）不同细胞类型和大脑区域中 MAPT 表达的动态，并评估了 tau 细胞病理学是否会影响 PSP 中的 MAPT 表达（n=3）。MAPT 转录本在神经元、星形胶质细胞和少突胶质细胞中均有检测到，并且在不同的大脑区域和每个细胞类型之间都有所不同，并且在 PSP 中所有具有 tau 聚集体的细胞类型中都得到了保留。这些结果提出了一种复杂的情况，即在所有细胞类型中，除了摄取的错误折叠的 tau 之外，保留的细胞 MAPT 表达为局部蛋白质产生提供了一个池，这些蛋白质可以（1）被磷酸化和聚集，或者（2）通过提供生理 tau 来为摄取的错误折叠 tau 的播种提供养分，从而加剧病理过程。由于 PSP 中的 tau 细胞病理学并不影响 MAPT 基因表达，因此早期致病成分中 tau 蛋白完全缺失的可能性较小。这些观察结果为通过降低细胞 MAPT 表达和靶向清除错误折叠 tau 来进行双重治疗提供了依据。
