Aranda-Abreu Gonzalo Emiliano, Rojas-Durán Fausto, Hernández-Aguilar María Elena, Herrera-Covarrubias Deissy, García-Hernández Luis Isauro, Toledo-Cárdenas María Rebeca, Chi-Castañeda Donají
Instituto de Investigaciones Cerebrales, Universidad Veracruzana, Av. Luis Castelazo Ayala s/n, Col. Industrial Animas, Xalapa 91190, Mexico.
Neurol Int. 2025 May 13;17(5):75. doi: 10.3390/neurolint17050075.
Tau protein plays a pivotal role in maintaining neuronal structure and function through its regulation of microtubule stability and neuronal polarity. Encoded by the gene, Tau exists in multiple isoforms due to alternative mRNA splicing, with differential expression in the central and peripheral nervous systems. In healthy neurons, mRNA is selectively localized and translated in axons, a process tightly regulated by untranslated regions (UTRs) and RNA-binding proteins such as HuD and FMRP. Pathologically, Tau undergoes hyperphosphorylation, misfolding, and aggregation, which contribute to neurodegeneration in a range of disorders collectively known as tauopathies. Alzheimer's disease (AD) is the most prevalent tauopathy, where abnormal Tau accumulation in the temporal and frontal lobes correlates with cognitive decline and behavioral symptoms. Other tauopathies, including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Frontotemporal Dementia with Parkinsonism (FTDP-17), and Pick's disease, are distinguished by the predominance of specific Tau isoforms (3R or 4R), cellular distribution, and affected brain regions. Notably, astroglial tauopathies highlight the pathological role of Tau accumulation in glial cells, expanding the understanding of neurodegeneration beyond neurons. Despite advances in imaging biomarkers (e.g., Tau-PET) and molecular diagnostics, effective disease-modifying therapies for tauopathies remain elusive. Ongoing research targets Tau through immunotherapies, splicing modulators, kinase inhibitors, and antisense oligonucleotides, aiming to mitigate Tau pathology and its deleterious effects. Understanding the multifaceted roles of Tau in neuronal and glial contexts is critical for developing future therapeutic strategies against tauopathies.
tau蛋白通过调节微管稳定性和神经元极性在维持神经元结构和功能中发挥关键作用。由该基因编码，由于mRNA可变剪接，tau存在多种异构体，在中枢和外周神经系统中表达不同。在健康神经元中，mRNA选择性地定位于轴突并在轴突中翻译，这一过程受非翻译区（UTRs）和RNA结合蛋白如HuD和FMRP的严格调控。在病理情况下，tau会发生过度磷酸化、错误折叠和聚集，这在一系列统称为tau蛋白病的疾病中导致神经退行性变。阿尔茨海默病（AD）是最常见的tau蛋白病，颞叶和额叶中异常的tau积累与认知衰退和行为症状相关。其他tau蛋白病，包括进行性核上性麻痹（PSP）、皮质基底节变性（CBD）、伴有帕金森综合征的额颞叶痴呆（FTDP-17）和皮克病，其特点是特定tau异构体（3R或4R）的优势、细胞分布和受影响的脑区。值得注意的是，星形胶质细胞tau蛋白病突出了tau积累在胶质细胞中的病理作用，扩展了对神经退行性变的理解，超越了神经元。尽管成像生物标志物（如tau-PET）和分子诊断取得了进展，但针对tau蛋白病的有效疾病修饰疗法仍然难以捉摸。正在进行的研究通过免疫疗法、剪接调节剂、激酶抑制剂和反义寡核苷酸靶向tau，旨在减轻tau病理及其有害影响。了解tau在神经元和胶质细胞环境中的多方面作用对于开发未来针对tau蛋白病的治疗策略至关重要。
