INTRODUCTIONAlternative splicing of the human MAPT gene generates six brain‐specific TAU isoforms. Imbalances in the TAU isoform ratio can lead to neurodegenerative diseases, underscoring the need for precise control over TAU isoform balance. Tauopathies, characterized by intracellular aggregates of hyperphosphorylated TAU, exhibit extensive neurodegeneration and can be classified by the TAU isoforms present in pathological accumulations.METHODSA comprehensive review of TAU and related dementia syndromes literature was conducted using PubMed, Google Scholar, and preprint server.RESULTSWhile TAU is recognized as key driver of neurodegeneration in specific tauopathies, the contribution of the isoforms to neuronal function and disease development remains largely elusive.DISCUSSIONIn this review we describe the role of TAU isoforms in health and disease, and stress the importance of comprehending and studying TAU isoforms in both, physiological and pathological context, in order to develop targeted therapeutic interventions for TAU‐associated diseases.Highlights MAPT splicing is tightly regulated during neuronal maturation and throughout life. TAU isoform expression is development‐, cell‐type and brain region specific. The contribution of TAU to neurodegeneration might be isoform‐specific. Ineffective TAU‐based therapies highlight the need for specific targeting strategies.

中文翻译：

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六种大脑特异性 TAU 亚型及其在阿尔茨海默病和相关神经退行性痴呆综合征中的作用

引言 人类的选择性剪接MAPT基因产生六种大脑特异性 TAU 亚型。 TAU 同工型比例失衡可导致神经退行性疾病，这凸显了精确控制 TAU 同工型平衡的必要性。 TAU 病以细胞内过度磷酸化 TAU 聚集为特征，表现出广泛的神经变性，可以根据病理积累中存在的 TAU 同工型进行分类。方法使用 PubMed、Google Scholar 和预印本服务器对 TAU 和相关痴呆综合征文献进行全面回顾。 TAU 被认为是特定 tau 病中神经变性的关键驱动因素，但异构体对神经元功能和疾病发展的贡献在很大程度上仍然难以捉摸。讨论在这篇综述中，我们描述了 TAU 异构体在健康和疾病中的作用，并强调理解和研究 TAU 的重要性生理和病理背景下的亚型，以便开发针对 TAU 相关疾病的有针对性的治疗干预措施。亮点 MAPT剪接在神经元成熟期间和整个生命过程中受到严格调节。 TAU 同工型表达具有发育、细胞类型和大脑区域特异性。 TAU 对神经退行性变的贡献可能是异构体特异性的。 基于 TAU 的无效疗法凸显了对特定靶向策略的需求。