Astrocytes Become Inflammatory in the Aging Brain

Astrocytes are one of the common types of support cell in the brain, performing a wide variety of tasks that range from repair to maintaining the balance of various signal and electrolyte molecules. Researchers find evidence to suggest that astrocytes shift into an inflammatory mode in large numbers with advancing age. Chronic inflammation is a feature of most neurodegenerative conditions, and of aging in the broader sense. It disrupts the complex relationships between cell types that are needed for most sophisticated behavior in tissues, such as regeneration, or any number of cell communication processes required for correct function of the brain.

This is particularly interesting in the context of recent findings regarding cellular senescence in astrocytes. A large fraction of these cells show some signs of senescence in older individuals, and one of the characteristic bad behaviors of senescent cells is the generation of chronic inflammation through the senescence-associated secretory phenotype. Researchers have pinned down astrocyte senescence as a contributing factor in Parkinson's disease, for example. It is also worth noting that this business of cells shifting into an inflammatory mode in greater numbers with advancing age is also observed in macrophages, where it disrupts regenerative processes, and in microglia, another of the support cells of the brain. They also generate chronic inflammation in brain tissue, which contributes to the complicated breakdown of the normal operation of the brain.

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 performed 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.

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.

Link: https://doi.org/10.1073/pnas.1800165115

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