Normal aging induces A1-like astrocyte reactivity

By L. Clarke, S. A. Liddelow, C. Chakraborty, Alexandra E. Münch, M. Heiman, B. Barres. Proceedings of the National Academy of Sciences of the United States of America, 2018

1,118 citations recorded by the source corpus.

Significance In aging, the brain becomes vulnerable to injury and cognitive function declines, but the mechanisms responsible are unknown. Astrocytes, the most abundant class of glial cells, are vital for the proper function of the central nervous system, and impairment of astrocyte function has been implicated in disease. Here we perform RNA sequencing of astrocytes from different brain regions across the lifespan of the mouse to identify age-related transcriptional changes that could contribute to cognitive decline. We find that aged astrocytes take on a reactive phenotype characteristic of neuroinflammatory reactive astrocytes, and that microglia play a role in inducing astrocyte activation. The aging astrocyte RNA sequencing profiles provide an important new resource for future studies exploring the role of astrocytes in cognitive decline. The decline of cognitive function occurs with aging, but the mechanisms responsible are unknown. Astrocytes instruct the formation, maturation, and elimination of synapses, and impairment of these functions has been implicated in many diseases. These findings raise the question of whether astrocyte dysfunction could contribute to cognitive decline in aging. We used the Bac-Trap method to perform RNA sequencing of astrocytes from different brain regions across the lifespan of the mouse. We found that astrocytes have region-specific transcriptional identities that change with age in a region-dependent manner. We validated our findings using fluorescence in situ hybridization and quantitative PCR. Detailed analysis of the differentially expressed genes in aging revealed that aged astrocytes take on a reactive phenotype of neuroinflammatory A1-like reactive astrocytes. Hippocampal and striatal astrocytes up-regulated a greater number of reactive astrocyte genes compared with cortical astrocytes. Moreover, aged brains formed many more A1 reactive astrocytes in response to the neuroinflammation inducer lipopolysaccharide. We found that the aging-induced up-regulation of reactive astrocyte genes was significantly reduced in mice lacking the microglial-secreted cytokines (IL-1α, TNF, and C1q) known to induce A1 reactive astrocyte formation, indicating that microglia promote astrocyte activation in aging. Since A1 reactive astrocytes lose the ability to carry out their normal functions, produce complement components, and release a toxic factor which kills neurons and oligodendrocytes, the aging-induced up-regulation of reactive genes by astrocytes could contribute to the cognitive decline in vulnerable brain regions in normal aging and contribute to the greater vulnerability of the aged brain to injury.

View Paper: https://www.semanticscholar.org/paper/5fe431a516bb91a9ee34436ea264eeaacedf9de6

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1. Tiantian Guo
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3. Yuzhe Zeng
4. Timothy Y. Huang
5. Huaxi Xu
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7. Yingjun Zhao
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Citations in the corpus

• Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer (2020, background): “In the brain, BDNF is expressed by glutamatergic neurons [1], glial cells, such as astrocytes isolated from the cortex and hippocampus, but not from the striatum [2], and microglia [3].”
• Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “Indeed, A1-astrocytes are abundantly prominent in aged brain under both normal and LPS stimulated conditions [525].”