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多模态转录组学揭示了齿状回中的神经源性衰老轨迹和与年龄相关的局部炎症。

Multimodal transcriptomics reveal neurogenic aging trajectories and age-related regional inflammation in the dentate gyrus.

作者信息

Wu Yicheng, Korobeynyk Vladyslav I, Zamboni Margherita, Waern Felix, Cole John Darby, Mundt Sarah, Greter Melanie, Frisén Jonas, Llorens-Bobadilla Enric, Jessberger Sebastian

机构信息

Laboratory of Neural Plasticity, Faculties of Medicine and Science, Brain Research Institute, University of Zurich, Zurich, Switzerland.

Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.

出版信息

Nat Neurosci. 2025 Feb;28(2):415-430. doi: 10.1038/s41593-024-01848-4. Epub 2025 Jan 6.

DOI:10.1038/s41593-024-01848-4
PMID:39762661
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11802457/
Abstract

The mammalian dentate gyrus (DG) is involved in certain forms of learning and memory, and DG dysfunction has been implicated in age-related diseases. Although neurogenic potential is maintained throughout life in the DG as neural stem cells (NSCs) continue to generate new neurons, neurogenesis decreases with advancing age, with implications for age-related cognitive decline and disease. In this study, we used single-cell RNA sequencing to characterize transcriptomic signatures of neurogenic cells and their surrounding DG niche, identifying molecular changes associated with neurogenic aging from the activation of quiescent NSCs to the maturation of fate-committed progeny. By integrating spatial transcriptomics data, we identified the regional invasion of inflammatory cells into the hippocampus with age and show here that early-onset neuroinflammation decreases neurogenic activity. Our data reveal the lifelong molecular dynamics of NSCs and their surrounding neurogenic DG niche with age and provide a powerful resource to understand age-related molecular alterations in the aging hippocampus.

摘要

哺乳动物的齿状回（DG）参与特定形式的学习和记忆，并且DG功能障碍与年龄相关疾病有关。尽管随着神经干细胞（NSCs）持续产生新的神经元，DG在整个生命过程中都保持着神经发生潜能，但神经发生会随着年龄的增长而减少，这与年龄相关的认知衰退和疾病有关。在本研究中，我们使用单细胞RNA测序来表征神经发生细胞及其周围DG生态位的转录组特征，确定从静止NSCs的激活到命运确定后代的成熟过程中与神经发生衰老相关的分子变化。通过整合空间转录组学数据，我们确定了随着年龄增长炎症细胞向海马体的区域浸润，并在此表明早发性神经炎症会降低神经发生活性。我们的数据揭示了NSCs及其周围神经发生的DG生态位随年龄变化的终身分子动态，并为理解衰老海马体中与年龄相关的分子改变提供了强大的资源。

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