MICROGLIA AGING IN THE HIPPOCAMPUS ADVANCES THROUGH INTERMEDIATE STATES THAT DRIVE INFLAMMATORY ACTIVATION AND COGNITIVE DECLINE.
MICROGLIA AGING IN THE HIPPOCAMPUS ADVANCES THROUGH INTERMEDIATE STATES THAT DRIVE INFLAMMATORY ACTIVATION AND COGNITIVE DECLINE.
复制标题
海马体中的小胶质细胞老化通过中间状态进展，从而驱动炎症激活和认知衰退。
DOI：
10.1101/2024.04.09.588665
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Villeda,SaulA
中科院分区：
文献类型：
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作者：
Shea,JeremyM;Villeda,SaulA
在衰老过程中，小胶质细胞——驻留在大脑中的巨噬细胞——表现出营养不良的表型，并导致与年龄相关的神经炎症。虽然许多与年龄相关的小胶质细胞营养不良的特征已经被阐明，但在衰老过程中从体内平衡到功能障碍的进展仍未得到解决。为了弥补这方面的知识差距，我们对小鼠海马中的小胶质细胞进行了补充的细胞和分子分析，分析了小鼠成年期和异慢性异种共生的实验衰老模型。单细胞RNA-Seq和伪时间分析揭示了海马小胶质细胞与年龄相关的转录异质性，并确定了异慢性异种共生后也出现的小胶质细胞衰老的中间状态。我们通过体外药理学方法测试了tgf - β1和翻译状态的中间应激反应状态的功能，揭示了它们对炎症状态进展的调节。此外，我们利用单细胞RNA-Seq结合活体成年小胶质细胞特异性tgfb1条件基因敲除小鼠模型，证明小胶质细胞通过中间衰老状态的进展驱动炎症激活和相关的海马依赖性认知衰退。
During aging, microglia – the resident macrophages of the brain – exhibit dystrophic phenotypes and contribute to age-related neuroinflammation. While numerous hallmarks of age-related microglia dystrophy have been elucidated, the progression from homeostasis to dysfunction during the aging process remains unresolved. To bridge this gap in knowledge, we undertook complementary cellular and molecular analyses of microglia in the mouse hippocampus across the adult lifespan and in the experimental aging model of heterochronic parabiosis. Single-cell RNA-Seq and pseudotime analysis revealed age-related transcriptional heterogeneity in hippocampal microglia and identified intermediate states of microglial aging that also emerge following heterochronic parabiosis. We tested the functionality of intermediate stress response states via TGFβ1 and translational states using pharmacological approachesin vitroto reveal their modulation of the progression to an inflammatory state. Furthermore, we utilized single-cell RNA-Seq in conjunction with anin vivoadult microglia-specificTgfb1conditional genetic knockout mouse model, to demonstrate that microglia advancement through intermediate aging states drives inflammatory activation and associated hippocampal-dependent cognitive decline.