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 (9): 4424-4434.doi: 10.4103/NRR.NRR-D-25-00195

• 原著:退行性病与再生 • 上一篇    下一篇

神经干细胞源性细胞外囊泡调节小胶质细胞增强对tau寡聚体的抵抗力#br#
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  • 出版日期:2026-09-15 发布日期:2026-05-22

Hippocampal neural stem cell–derived extracellular vesicles modulate microglia to promote resilience against tau oligomers

Salvatore Saieva1, †, Pietro Scaduto1, ‡, Anna Fracassi1, Jutatip Guptarak1, Wen-Ru Zhang1, Kathia Johnson2, Daniel C. Jupiter3, Michela Marcatti1, Olga Zolochevska1, Giulio Taglialatela1, *, #, Maria-Adelaide Micci2, *, #   

  1. 1Mitchell Center for Neurodegenerative Diseases, Department of Neurology, The University of Texas Medical Branch, Galveston, TX, USA; 
    2Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA; 
    3Department of Biostatistics & Data Science, Department of Orthopaedic Surgery and Rehabilitation, The University of Texas Medical Branch (UTMB), Galveston, TX, USA

  • Online:2026-09-15 Published:2026-05-22
  • Contact: Giulio Taglialatela, PhD, gtaglial@utmb.edu; Maria Adelaide Micci, PhD, mmicci@utmb.edu.
  • Supported by:
     This work was supported by NIA/NIH 5R01AG069433 (to MAM and GT).

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摘要：

阿尔茨海默病的特征之一是海马齿状回中神经干细胞数量减少。尽管神经干细胞数量增加常与学习记忆能力提升相关，但单纯的神经发生并不能始终维持这些功能，表明存在其他涉及神经干细胞的记忆支持机制。先前研究表明，向野生型小鼠脑室内注射神经干细胞来源的小胞外囊泡可减轻认知衰退并减少毒性寡聚体与突触的结合。实验假设充足的神经干细胞数量能支持神经干细胞源性细胞外囊泡保护突触免受阿尔茨海默病毒性寡聚体侵害。揭示了中枢神经系统免疫反应的组成部分（尤其是小胶质细胞）可能参与了这种保护作用。具体而言，向野生型小鼠脑内注射荧光标记的神经干细胞源性细胞外囊泡后，小胶质细胞摄取了这些囊泡，其中仅神经干细胞源性细胞外囊泡导致小胶质细胞活化增强（通过CD68免疫染色证实）。RNA测序数据表明，神经干细胞源性细胞外囊泡选择性激活小胶质细胞的免疫通路，导致给药24h后小胶质细胞活化增强且Tau蛋白摄取量升高。海马区小胶质细胞单核RNA测序揭示其基因表达受溶酶体活性调控，证实神经干细胞源性细胞外囊泡通过小胶质细胞介导神经保护作用。实验揭示了神经干细胞源性细胞外囊泡增强小胶质细胞活性并提供海马神经保护的新机制。数据表明，小胶质细胞摄取神经干细胞源性细胞外囊泡可增强其自身活化并提高对Tau寡聚体的摄取效率，暗示神经干细胞源性细胞外囊泡可能通过预先激活小胶质细胞来增强免疫应答效能。这些结果支持以下假说：神经干细胞-小细胞外囊泡诱导的小胶质细胞功能调节对维持神经元完整性及缓解神经退行性病变至关重要。通过阐明神经干细胞源性细胞外囊泡与小胶质细胞的相互作用，从而为开发增强小胶质细胞功能的治疗策略开辟了新途径，有望应对阿尔茨海默病等神经退行性疾病。


https://orcid.org/0000-0003-4795-447X (Giulio Taglialatela); https://orcid.org/0000-0001-6689-2994 (Maria Adelaide Micci)

关键词: 阿尔茨海默病l海马l免疫反应l溶酶体l小胶质细胞l神经干细胞l神经炎症l单核RNA测序l小胞外囊泡lTau寡聚体

Abstract: Neural stem cells and adult hippocampal neurogenesis modulate synaptic plasticity and cognitive function. Neural stem cells secrete extracellular vesicles – microvesicles carrying biomolecular cargos – that modulate the function of other cells and contribute to homeostasis and plasticity in the central nervous system. Alzheimer’s disease is marked by a reduction of neural stem cells in the hippocampus dentate gyrus. While increased neural stem cells often correlate with better learning and memory, neurogenesis alone does not always preserve these processes, indicating that other mechanisms involving neural stem cells support memory. It has been shown that intracerebroventricular delivery of neural stem cell-derived small extracellular vesicles in wild-type mice reduces cognitive decline and toxic oligomer binding to synapses. We hypothesize that adequate neural stem cell numbers support neural stem cell–derived small extracellular vesicles protection of synapses against Alzheimer’s disease toxic oligomers. Here, we show that elements of immune response in the central nervous system, particularly microglia, may contribute to this protective effect. Specifically, fluorescence-labeled small extracellular vesicles injected into wild-type mice brains were taken up by microglia, with only neural stem cell–derived small extracellular vesicles causing increased microglial activation, indicated by CD68 immunostaining. RNA-sequencing data showed selective activation of immune pathways in microglia by neural stem cell-derived small extracellular vesicles, leading to greater activation and higher Tau uptake 24 hours post-neural stem cell–derived small extracellular vesicle administration. Single-nuclei RNA-sequencing of hippocampal microglia gene revealed modulation related to lysosomal activity, supporting neural stem cell–derived small extracellular vesicle-induced neuroprotection via microglia. This study uncovers a novel mechanism through which neural stem cell–derived small extracellular vesicles enhance microglial activity and provide neuroprotection in the hippocampus. Our data demonstrates that neural stem cell–derived small extracellular vesicle uptake by microglia leads to increased microglial activation and improved uptake of Tau oligomers by microglia, suggesting that neural stem cell–derived small extracellular vesicles may prime microglia for a more effective immune response. These results support the hypothesis that neural stem cell–derived small extracellular vesicle-induced modulation of microglial function is crucial for preserving neuronal integrity and mitigating neurodegenerative processes. By elucidating the interactions between neural stem cell–derived small extracellular vesicles and microglia, our study opens new avenues for developing therapeutic strategies aimed at boosting microglial function and addressing neurodegenerative diseases such as Alzheimer’s disease.

Key words: Alzheimer’s diseasel hippocampusl immune responsel lysosomesl microglial neural stem cellsl neuroinflammationl single-nuclei RNA sequencingl small extracellular vesiclesl Tau oligomers