Tau, one of the most abundant microtubule-associated protein in neurons plays a role in regulating microtubule dynamics in axons, as well as shaping the overall morphology of the axon. Recent studies challenge the traditional view of tau as a microtubule stabilizer and shed new light on the complexity of its role in regulating various properties of the microtubule. While reducing tau levels shows therapeutic promise for early tauopathies, efficacy wanes in later stages due to resilient toxic tau aggregates and neurofibrillary tangles. Notably, tauopathies involve factors beyond toxic tau alone, necessitating a broader therapeutic approach. Overexpression of human tau in mouse models, although useful for answering some questions, may not accurately reflect disease mechanisms in patients with tauopathies. Furthermore, the interplay between tau and MAP6, another microtubule-associated protein, adds complexity to tau's regulation of microtubule dynamics. Tau promotes the formation and elongation of labile microtubule domains, vital for cellular processes, while MAP6 stabilizes microtubules. A delicate balance between these proteins is important for neuronal function. Therefore, tau reduction therapies require a comprehensive understanding of disease progression, considering functional tau loss, toxic aggregates, and microtubule dynamics. Stage-dependent application and potential unintended consequences must be carefully evaluated. Restoring microtubule dynamics in late-stage tauopathies may necessitate alternative strategies. This knowledge is valuable for developing effective and safe treatments for tauopathies.

中文翻译：

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重新评估 tau 蛋白减少作为 tau 蛋白病的治疗方法：见解和观点

Tau 是神经元中最丰富的微管相关蛋白之一，在调节轴突微管动力学以及塑造轴突的整体形态方面发挥着作用。最近的研究挑战了 tau 作为微管稳定剂的传统观点，并为它在调节微管各种特性方面的复杂性提供了新的线索。虽然降低 tau 水平显示出对早期 tau 病的治疗前景，但由于弹性有毒 tau 聚集体和神经原纤维缠结，疗效在后期逐渐减弱。值得注意的是，tau蛋白病涉及的因素不仅仅是有毒的tau蛋白本身，因此需要更广泛的治疗方法。人类 tau 在小鼠模型中的过度表达虽然有助于回答一些问题，但可能无法准确反映 tau 病患者的疾病机制。此外，tau 和另一种微管相关蛋白 MAP6 之间的相互作用增加了 tau 对微管动力学调节的复杂性。Tau 促进不稳定微管结构域的形成和延长，这对细胞过程至关重要，而 MAP6 则稳定微管。这些蛋白质之间的微妙平衡对于神经元功能非常重要。因此，tau 减少疗法需要全面了解疾病进展，考虑功能性 tau 丢失、毒性聚集体和微管动力学。必须仔细评估阶段相关的应用和潜在的意外后果。在晚期 tau蛋白病中恢复微管动力学可能需要替代策略。这些知识对于开发有效且安全的 tau蛋白病治疗方法非常有价值。