Microtubule-associated protein tau is abnormally aggregated in neuronal and glial cells in a range of neurodegenerative diseases that are collectively referred to as tauopathies. Multiple studies have suggested that pathological tau species may act as a seed that promotes aggregation of endogenous tau in naïve cells and contributes to propagation of tau pathology. While they share pathological tau aggregation as a common feature, tauopathies are distinct from one another with respect to predominant tau isoforms that accumulate and the selective vulnerability of brain regions and cell types that have tau inclusions. For instance, primary tauopathies present with glial tau pathology, while it is mostly neuronal in Alzheimer’s disease (AD). Also, morphologies of tau inclusions can greatly vary even within the same cell type, suggesting distinct mechanisms or distinct tau conformers in each tauopathy. Neuropathological heterogeneity across tauopathies challenges our understanding of pathophysiology behind tau seeding and aggregation, as well as our efforts to develop effective therapeutic strategies for AD and other tauopathies. In this review, we describe diverse neuropathological features of tau inclusions in neurodegenerative tauopathies and discuss what has been learned from experimental studies with mouse models, advanced transcriptomics, and cryo-electron microscopy (cryo-EM) on the biology underlying cell type-specific tau pathology.

中文翻译：

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原发性tau蛋白病的细胞和病理异质性

在一系列统称为 tau 病的神经退行性疾病中，微管相关蛋白 tau 异常聚集在神经元和神经胶质细胞中。多项研究表明，病理性 tau 物种可能充当种子，促进内源性 tau 在幼稚细胞中聚集，并有助于 tau 病理学的传播。虽然它们具有病理性 tau 聚集这一共同特征，但 tau 病在累积的主要 tau 异构体以及具有 tau 内含物的大脑区域和细胞类型的选择性脆弱性方面彼此不同。例如，原发性 tau 蛋白病表现为神经胶质 tau 蛋白病理，而阿尔茨海默病 (AD) 中的病理主要是神经元性的。此外，即使在相同的细胞类型中，tau 内含物的形态也可能有很大差异，这表明每种 tau 蛋白病变中存在不同的机制或不同的 tau 构象异构体。tau蛋白病的神经病理学异质性挑战了我们对tau蛋白播种和聚集背后病理生理学的理解，也挑战了我们为AD和其他tau蛋白病开发有效治疗策略的努力。在这篇综述中，我们描述了神经退行性 tau 病中 tau 包涵体的不同神经病理学特征，并讨论了从小鼠模型、高级转录组学和冷冻电子显微镜 (cryo-EM) 的实验研究中学到的关于细胞类型特异性 tau 的生物学基础的知识病理。