Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, École Polytechnique Federal de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, École Polytechnique Federal de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
Neurobiol Dis. 2021 Dec;161:105536. doi: 10.1016/j.nbd.2021.105536. Epub 2021 Oct 27.
The accumulation of hyperphosphorylated fibrillar Tau aggregates in the brain is one of the defining hallmarks of Tauopathy diseases, including Alzheimer's disease. However, the primary events or molecules responsible for initiation of the pathological Tau aggregation and spreading remain unknown. The discovery of heparin as an effective inducer of Tau aggregation in vitro was instrumental to enabling different lines of research into the role of Tau aggregation in the pathogenesis of Tauopathies. However, recent proteomics and cryogenic electron microscopy (cryo-EM) studies have revealed that heparin-induced Tau fibrils generated in vitro do not reproduce the biochemical and ultrastructural properties of disease-associated brain-derived Tau fibrils. These observations demand that we reassess our current approaches for investigating the mechanisms underpinning Tau aggregation and pathology formation. Our review article presents an up-to-date survey and analyses of 1) the evolution of our understanding of the interactions between Tau and heparin, 2) the various structural and mechanistic models of the heparin-induced Tau aggregation, 3) the similarities and differences between brain-derived and heparin-induced Tau fibrils; and 4) emerging concepts on the biochemical and structural determinants underpinning Tau pathological heterogeneity in Tauopathies. Our analyses identify specific knowledge gaps and call for 1) embracing the complexities of Tau pathologies; 2) reassessment of current approaches to investigate, model and reproduce pathological Tau aggregation as it occurs in the brain; 3) more research towards a better understanding of the naturally-occurring cofactor molecules that are associated with Tau brain pathology initiation and propagation; and 4) developing improved approaches for in vitro production of the Tau aggregates and fibrils that recapitulate and/or amplify the biochemical and structural complexity and diversity of pathological Tau in Tauopathies. This will result in better and more relevant tools, assays, and mechanistic models, which could significantly improve translational research and the development of drugs and antibodies that have higher chances for success in the clinic.
脑中过度磷酸化纤维状 Tau 聚集体的积累是 Tau 病的标志性特征之一，包括阿尔茨海默病。然而，导致病理性 Tau 聚集和扩散的初始事件或分子仍不清楚。肝素作为体外诱导 Tau 聚集的有效物质的发现，对于研究 Tau 聚集在 Tau 病发病机制中的作用起到了重要作用。然而，最近的蛋白质组学和低温电子显微镜（cryo-EM）研究表明，体外诱导产生的肝素诱导 Tau 纤维并不再现与疾病相关的脑源性 Tau 纤维的生化和超微结构特性。这些观察结果要求我们重新评估我们目前研究 Tau 聚集和病理形成机制的方法。我们的综述文章介绍了对以下内容的最新调查和分析：1）我们对 Tau 与肝素相互作用的理解的演变，2）肝素诱导 Tau 聚集的各种结构和机制模型，3）脑源性和肝素诱导 Tau 纤维之间的相似性和差异；4）在 Tau 病中 Tau 病理异质性的生化和结构决定因素方面的新兴概念。我们的分析确定了特定的知识空白，并呼吁：1）接受 Tau 病的复杂性；2）重新评估当前研究、建模和再现大脑中发生的病理性 Tau 聚集的方法；3）进行更多的研究，以更好地理解与 Tau 脑病理起始和传播相关的天然存在的辅助因子分子；4）开发更好的体外生产 Tau 聚集体和纤维的方法，这些方法可以再现和/或放大 Tau 病中 Tau 的生化和结构复杂性和多样性。这将导致更好和更相关的工具、检测和机制模型，从而可以显著改善转化研究以及开发在临床上更有可能成功的药物和抗体。
