小胶质细胞
陶氏病
神经退行性变
生物
人口
S100A9型
转录组
特雷姆2
共域化
表型
衰老
神经炎症
神经科学
S100A8型
认知功能衰退
免疫染色
免疫学
病理
炎症
细胞生物学
基因
疾病
遗传学
基因表达
医学
免疫组织化学
痴呆
环境卫生
作者
Roxane Gruel,Baukje Bijnens,Johanna Van Daele,Sofie Thys,Roland Willems,D. Wuyts,Debby Van Dam,Peter Verstraelen,Rosanne Verboven,Jana Roels,Niels Vandamme,Renzo Mancuso,Jaun Diego Pita-Almenar,Winnok H. De Vos
标识
DOI:10.1101/2023.11.10.566543
摘要
Abstract Long considered to fluctuate between pro- and anti-inflammatory states, it has now become evident that microglia occupy a variegated phenotypic landscape with relevance to aging and neurodegeneration. However, whether specific microglial subsets converge in or contribute to both processes that eventually affect brain function is less clear. To investigate this, we analyzed microglial heterogeneity in a tauopathy mouse model (K18-seeded P301L) and an accelerated aging model (senescence accelerated mouse prone 8, SAMP8) using cellular indexing of transcriptomes and epitopes by sequencing. We found that widespread tau pathology in K18-seeded P301L mice caused a significant change in the number and morphology of microglia, but only a mild overrepresentation of disease-associated microglia. At the cell population-level, we observed a marked upregulation of the calprotectin-encoding genes S100a8 and S100a9 . In 9-months-old SAMP8 mice, we identified a unique microglial subpopulation that showed partial similarity with the disease-associated microglia phenotype and was additionally characterized by a high expression of the same calprotectin gene set. Immunostaining for S100A8 revealed that this population was enriched in the hippocampus, correlating with the cognitive impairment observed in this model. However, incomplete colocalization between their residence and markers of neuronal loss suggests regional specificity. Importantly, S100A8-positive microglia were also retrieved in brain biopsies of human AD and tauopathy patients as well as in a biopsy of an aged individual without reported pathology. Thus, the emergence of S100A8-positive microglia portrays a conspicuous commonality between accelerated aging and tauopathy progression, which may have relevance for ensuing brain dysfunction. Graphical abstract
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