Astrocyte senescence promotes glutamate toxicity in cortical neurons

• Published in: PloS one Vol. 15; no. 1; p. e0227887
• Main Authors: Limbad, Chandani, Oron, Tal Ronnen, Alimirah, Fatouma, Davalos, Albert R, Tracy, Tara E, Gan, Li, Desprez, Pierre-Yves, Campisi, Judith
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.01.2020; Public Library of Science (PLoS)
• Subjects: Age; Aging; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amino Acid Transport System X-AG - genetics; Amino acids; astocytes; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; BASIC BIOLOGICAL SCIENCES; Biology and Life Sciences; Brain - metabolism; Brain - pathology; Brain research; Cancer patients; Cancer treatment; Cell culture; Cell cycle; Cell Cycle Checkpoints - radiation effects; Cell death; Cell fate; Cell survival; Cellular Senescence - genetics; Cellular Senescence - radiation effects; Chemotherapy; Cognitive ability; Cortex; Dementia; Disease; Excitotoxicity; Fate; Fibroblasts; gene expression; Gene Expression Regulation - radiation effects; Gene sequencing; Genes; Genotype & phenotype; Glutamate; Glutamic Acid - genetics; Glutamic Acid - metabolism; Homeostasis; Humans; Immunoglobulins; Inflammation; Irradiation; Medicine and Health Sciences; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nervous system diseases; Neurodegeneration; Neurodegenerative diseases; neuronal death; Neurons; Neurons - metabolism; Neurons - pathology; Neurosciences; Phenotypes; Potassium; Primary Cell Culture; Research and analysis methods; Ribonucleic acid; RNA; RNA sequencing; Senescence; Toxicity; X radiation; X-Rays; Canada; United States > US; San Francisco California; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0227887

Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemo- or radio-therapies. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP). Although there is a link between inflammation and neurodegenerative diseases, there are many open questions regarding how cellular senescence affects neurodegenerative pathologies. Among the various cell types in the brain, astrocytes are the most abundant. Astrocytes have proliferative capacity and are essential for neuron survival. Here, we investigated the phenotype of primary human astrocytes made senescent by X-irradiation, and identified genes encoding glutamate and potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal cell death in co-culture assays. Unbiased RNA sequencing of transcripts expressed by non-senescent and senescent astrocytes confirmed that glutamate homeostasis pathway declines upon senescence. Our results suggest a key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration including Alzheimer's disease and related dementias.