中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (7): 3149-3155.doi: 10.4103/NRR.NRR-D-24-01598

• 原著:退行性病与再生 • 上一篇    下一篇

P301S Tau小鼠星形胶质细胞分泌组异常：阿尔茨海默病潜在生物标志物

  

  • 出版日期:2026-07-15 发布日期:2026-03-31

Astrocytes from P301S Tau mice exhibit non-canonical protein secretion and reduced morphological complexity

Aishwarya G. Nadadhur1, Matthew Mason1, Johanna S. Rees2, Marta Sidoryk-Wegrzynowicz1, 3, Aviva M. Tolkovsky1, *, Maria Grazia Spillantini1, *   

  1. 1Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK;  2Department of Biochemistry, University of Cambridge, Cambridge, UK;  3Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland
  • Online:2026-07-15 Published:2026-03-31
  • Contact: Aviva M. Tolkovsky, PhD, amt1004@cam.ac.uk; Maria Grazia Spillantini, PhD, mgs11@cam.ac.uk.
  • Supported by:
    This work was supported by grants to MGS from the Alzheimer Society (#384, AS-PG-17-026, Alzheimer’s Research UK (ART-PG2011-20 and ARUKEXT2015B-2), the BBSRC (BB/T509085/1), The Fondation Recherche Alzheimer (G112606), the Scholl Foundation, and to MGS and AMT from the National Center for the Replacement, Refinement, & Reduction of Animals in Research (NC3R) (#NC/L000741/1).

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摘要：

tau蛋白病是一组以tau蛋白异常聚集为特征的神经退行性疾病，包括阿尔茨海默病、额颞叶痴呆等。尽管tau蛋白的异常聚集与神经元死亡密切相关，但其具体毒性机制尚不清楚。P301S tau转基因小鼠（P301S小鼠）作为一种研究模型，能够模拟人类tau蛋白病的病理特征，为研究tau蛋白的毒性机制提供了重要工具。实验通过培养P301S小鼠和对照组小鼠（C57小鼠）的星形胶质细胞，比较了两组细胞培养液（ACM）中的蛋白质成分。利用无标记液相色谱-串联质谱（LC MS/MS）技术，详细分析了P301S-ACM和C57-ACM中的蛋白质组成。结果发现，P301S-ACM中约57%的富集蛋白为细胞质蛋白，这些蛋白与细胞代谢相关，且不通过经典或非经典分泌途径释放。相比之下，C57-ACM中约88%的富集蛋白为经典分泌蛋白，主要富集在细胞外基质成分中。此外，P301S小鼠的星形胶质细胞在体外培养时体积较小，且在体内表现出成熟度较低的特征。这些差异表明，P301S小鼠的星形胶质细胞可能通过一种非常规分泌途径释放蛋白质，这与Aβ暴露后的星形胶质细胞培养液（ACM）表现出相似的特征，提示tau蛋白和Aβ可能诱导了共同的不良反应途径。这一发现不仅揭示了P301S小鼠星形胶质细胞的异常分泌特征，还为阿尔茨海默病和其他tau蛋白病的临床诊断提供了潜在的生物标志物。

https://orcid.org/0000-0003-1951-3175 (Aviva M. Tolkovsky); 

https://orcid.org/0000-0002-8544-7332 (Maria Grazia Spillantini)

关键词: 星形胶质细胞条件培养基, 基础代谢, 细胞外基质, 神经元存活, P301S tau转基因小鼠, 结构成熟, tau, tau病, 非经典分泌, 标志物, 神经再生

Abstract:

Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms. We showed previously that astrocytes cultured from mice transgenic for human P301S-tau (P301S-mice) recapitulate the deficit in production and secretion of thrombospondin1 found in symptomatic P301S mouse brains, causing both reduced synapse formation and survival of cultured neurons. To further characterize how P301S-derived astrocytes differ from controls, we have compared the astrocyte-conditioned media of cultured astrocytes from postnatal day 7/8 P301S mice (P301S-astrocyte-conditioned media) versus controls (C57-astrocyte-conditioned media) using label-free liquid chromatography-mass spectrometry. We verified that thrombospondin1 secretion was significantly reduced in the P301S-astrocyte-conditioned media versus C57-astrocyte-conditioned media, demonstrating the robustness of the analysis. The most notable distinction was that ~57% of the P301S-astrocyte-conditioned media-enriched proteins were cytoplasmic proteins linked to cellular metabolism that are not predicted to be secreted via classical or non-classical secretion pathways, whereas ~88% of C57-astrocyte-conditioned media-enriched proteins comprised classically secreted proteins enriched in extracellular matrix components. These differences are associated with the finding that P301S-derived cultured astrocytes were smaller and in vivo appeared less mature in the cortex of P301S mice. The unconventional secretion pathway that P301S-astrocyte-conditioned media display shares similarities with several amyloid-β-exposed astrocyte-conditioned media, indicating that stimuli induced by tau and amyloid-β may induce a common adverse response pathway. Altogether, members of this adverse pathway may serve as a potential set of biomarkers to aid the clinical diagnosis of Alzheimer’s disease and other tauopathies, while the list of reduced neurosupportive factors could indicate new approaches to enhance neuronal survival by factor supplementation in tauopathies.

Key words: astrocyte conditioned medium, basal metabolism, extracellular matrix, nerve regeneration, neuronal survival, P301S tau transgenic mice, structural maturation, tau, tauopathy, unconventional secretion