Marvian Amir T, Strauss Tabea, Tang Qilin, Tuck Benjamin J, Keeling Sophie, Rüdiger Daniel, Mirzazadeh Dizaji Negar, Mohammad-Beigi Hossein, Nuscher Brigitte, Chakraborty Pijush, Sutherland Duncan S, McEwan William A, Köglsperger Thomas, Zahler Stefan, Zweckstetter Markus, Lichtenthaler Stefan F, Wurst Wolfgang, Schwarz Sigrid, Höglinger Günter
Department of Neurology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
German Center for Neurodegenerative Diseases (LMU), Klinikum, Germany.
Mol Neurodegener. 2024 Dec 31;19(1):100. doi: 10.1186/s13024-024-00786-w.
The prion-like spreading of Tau pathology is the leading cause of disease progression in various tauopathies. A critical step in propagating pathologic Tau in the brain is the transport from the extracellular environment and accumulation inside naïve neurons. Current research indicates that human neurons internalize both the physiological extracellular Tau (eTau) monomers and the pathological eTau aggregates. However, similarities or differences in neuronal transport mechanisms between Tau species remain elusive.
Monomers, oligomers, and fibrils of recombinant 2N4R Tau were produced and characterized by biochemical and biophysical methods. A neuronal eTau uptake and accumulation assay was developed for human induced pluripotent stem cell-derived neurons (iPSCNs) and Lund human mesencephalic cells (LUHMES)-derived neurons. Mechanisms of uptake and cellular accumulation of eTau species were studied by using small molecule inhibitors of endocytic mechanisms and siRNAs targeting Tau uptake mediators.
Extracellular Tau aggregates accumulated more than monomers in human neurons, mainly due to the higher efficiency of small fibrillar and soluble oligomeric aggregates in intraneuronal accumulation. A competition assay revealed a distinction in the neuronal accumulation between physiological eTau Monomers and pathology-relevant aggregates, suggesting differential transport mechanisms. Blocking heparan sulfate proteoglycans (HSPGs) with heparin only inhibited the accumulation of eTau aggregates, whereas monomers' uptake remained unaltered. At the molecular level, the downregulation of genes involved in HSPG synthesis exclusively blocked neuronal accumulation of eTau aggregates but not monomers, suggesting its role in the transport of pathologic Tau. Moreover, the knockdown of LRP1, as a receptor of Tau, mainly reduced the accumulation of monomeric form, confirming its involvement in Tau's physiological transport.
These data propose that despite the similarity in the cellular mechanism, the uptake and accumulation of eTau Monomers and aggregates in human neurons are regulated by different molecular mediators. Thus, they address the possibility of targeting the pathological spreading of Tau aggregates without disturbing the probable physiological or non-pathogenic transport of Tau Monomers.
Tau 病理的朊病毒样传播是各种 Tau 蛋白病疾病进展的主要原因。病理性 Tau 在大脑中传播的关键步骤是从细胞外环境转运并在未成熟神经元内积累。目前的研究表明，人类神经元会内化生理性细胞外 Tau（eTau）单体和病理性 eTau 聚集体。然而，不同 Tau 种类之间神经元转运机制的异同仍不清楚。
通过生化和生物物理方法制备并表征重组 2N4R Tau 的单体、寡聚体和原纤维。针对人诱导多能干细胞衍生神经元（iPSCNs）和隆德人脑中脑（LUHMES）衍生神经元开发了一种神经元 eTau 摄取和积累测定法。通过使用内吞机制的小分子抑制剂和靶向 Tau 摄取介质的 siRNA，研究了 eTau 种类的摄取和细胞积累机制。
细胞外 Tau 聚集体在人类神经元中的积累多于单体，主要是因为小纤维状和可溶性寡聚聚集体在神经元内积累的效率更高。竞争测定揭示了生理性 eTau 单体与病理相关聚集体在神经元积累方面的差异，表明转运机制不同。用肝素阻断硫酸乙酰肝素蛋白聚糖（HSPG）仅抑制 eTau 聚集体的积累，而单体的摄取保持不变。在分子水平上，参与 HSPG 合成的基因下调仅阻断 eTau 聚集体的神经元积累，而不影响单体，表明其在病理性 Tau 转运中的作用。此外，作为 Tau 受体的低密度脂蛋白受体相关蛋白 1（LRP1）的敲低主要减少了单体形式的积累，证实其参与 Tau 的生理性转运。
这些数据表明，尽管细胞机制相似，但人类神经元中 eTau 单体和聚集体的摄取和积累受不同分子介质的调节。因此，它们探讨了在不干扰 Tau 单体可能的生理性或非致病性转运的情况下，靶向 Tau 聚集体病理传播的可能性。
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