Role of Senescent Astrocytes in Health and Disease

Abstract

For many decades after their discovery, astrocytes, the abundant glial cells of the brain, were believed to work as a glue, supporting the structure and metabolic functions of neurons. A revolution that started over 30 years ago revealed many additional functions of these cells, including neurogenesis, gliosecretion, glutamate homeostasis, assembly and function of synapses, neuronal metabolism with energy production, and others. These properties have been confirmed, limited however, to proliferating astrocytes. During their aging or following severe brain stress lesions, proliferating astrocytes are converted into their no-longer-proliferating, senescent forms, similar in their morphology but profoundly modified in their functions. The changed specificity of senescent astrocytes is largely due to their altered gene expression. The ensuing effects include downregulation of many properties typical of proliferating astrocytes, and upregulation of many others, concerned with neuroinflammation, release of pro-inflammatory cytokines, dysfunction of synapses, etc., specific to their senescence program. The ensuing decrease in neuronal support and protection by astrocytes induces the development, in vulnerable brain regions, of neuronal toxicity together with cognitive decline. Similar changes, ultimately reinforced by astrocyte aging, are also induced by traumatic events and molecules involved in dynamic processes. Senescent astrocytes play critical roles in the development of many severe brain diseases. The first demonstration, obtained for Alzheimer’s disease less than 10 years ago, contributed to the elimination of the previously predominant neuro-centric amyloid hypothesis. The initial astrocyte effects, operating a considerable time before the appearance of known Alzheimer’s symptoms evolve with the severity of the disease up to their proliferation during the final outcome. Involvement of astrocytes in other neurodegenerative diseases and cancer is now intensely investigated.

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Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic–ischemic neonatal rats

“…Astrocytes, the most abundant cell type in the brain, play crucial roles in maintaining brain homeostasis. 46 Recent studies indicated that activated microglia can convert astrocytes into the neurotoxic A1 phenotype via the secretion of IL‐1α, TNF‐α, and C1q, and dysfunction of astrocytes critically impacts neuronal survival in various neurological diseases. 47 , 48 , 49 , 50 Previous studies, including our own, have demonstrated that DEX treatment effectively reduces microglial activation and subsequent neuroinflammation, improving neurological outcomes in neonatal rodents following HIBD.…”

Aging, NRF2, and TAU: A Perfect Match for Neurodegeneration?

“…Astrocytes, the most abundant glial cells within the CNS implicated in glutamate homeostasis and neurogenesis processes, are the metabolic and energetic support of neurons and are involved in synapse assembly and function, forming part of the tripartite synapse, among many other functions. During aging, these cells undergo changes in gene expression, leading to the appearance of senescent forms of astrocytes [ 76 ]. In contrast, microglial cells are the specific macrophages of the CNS that are specialized in phagocytizing apoptotic neurons, eliminating aggregated extracellular proteins, defending against infections, and pruning synapses, among other functions [ 77 ].…”