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Alterations of immune cells heterogeneities in the aged zebrafish brain at single-cell resolution II

ABSTRACT: Immune cells, the most core part of the immune system of the whole body, could rapidly response to the change of environment. Its roles in tissue homeostasis and disease were fairly clear except brain, an immune privilege site. Previous studies had revealed the contribution of microglia, a tissue-resident macrophage, for brain development and neuronal disease. But it was currently unknown whether the other subtypes of immune cells and which of the microglia populations program their function during different stages of development. Here, we analyzed the genes expression pattern of 26,456 immune cells from the whole zebrafish brain during adult and aged stage. Our analysis uncovered the present of lymphocyte in zebrafish brain, and gradually accumulated with aging. In addition, the number of microglia were reduced bute the diversity were increased in aged brain. Collectively, our data provide insights into zebrafish brain immune cells populations that explain the distinct composition of immune cells in adult and aged brain, which might contribute to understanding the roles of immune cells in aging-associated-disease.

ORGANISM(S): Danio rerio

PROVIDER: GSE197673 | GEO | 2023/01/12

REPOSITORIES: GEO

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Project description:The aging process is marked by a time-dependent deterioration in cellular functions, particularly the immune and neural systems. Understanding the phenotype acquisition of microglia, the sentinel immune cells of the brain, is crucial for understanding the nature of age-related neurological diseases. However, the specific phenotype adopted by microglia during aging remains a subject of debate and is contingent on the chosen experimental model. To address these unresolved questions, we employed a novel and highly controlled approach utilizing long-term cultivated BV-2 microglia, exempted of additional external stimuli. Our findings revealed that aged microglial cells, in comparison to their younger counterparts, acquire a distinct gene expression profile, primarily characterized by alterations in microglial immune response. Indeed, pro-inflammatory stimulated aged and young BV-2 microglia exhibited similar transcriptomic profiles, yet the response intensity to stimulus was markedly muted in the aged microglia. Functional neurotoxic assays confirmed diminished neuronal death in coculture with aged, activated microglia, underscoring a compromised immune response. Furthermore, a subsequent comparative analysis of aged BV-2 microglia with established transcriptomic microglial datasets from aged mice and humans identified 13 overlapping genes, laying the foundation for identifying core microglial aging signature. Particularly noteworthy were SLC16A3 and P2RY13, which consistently exhibited upregulation and downregulation, respectively, across all datasets. Additionally, four other genes—CAPG, LGALS3BP, NRIP1, and P2RY12—were found to share regulatory patterns in response to both aging and extrinsic activation. In-depth investigation focused on SLC16A3, encoding the high-affinity lactate transporter MCT4, revealed disruptions in extracellular acidification rate and lactate concentration with age. Microglial purine sensing and motility capacities, regulated by P2RY12/P2RY13, displayed age-related alterations. Remarkably, protein analysis in human brain tissue validated the observed upregulation of MCT4 and downregulation of P2RY12 in aged microglia. In conclusion, our study unveils a distinct phenotype in aged microglia characterized by compromised immune responsiveness. Through the integration of in vitro cultured BV-2 microglia with primary microglia datasets, we identify critical molecular determinants of microglial cellular aging confirmed in human aged brain tissue. This comprehensive approach offers potential insights for understanding and potentially reprogramming aged microglia, with implications for combating age-related neurological disorders.

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Alterations of immune cells heterogeneities in the aged zebrafish brain at single-cell resolution II

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