Astrocyte senescence promotes glutamate toxicity in cortical neurons

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ID: 271138
2020
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Abstract
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.
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Authors Chandani Limbad;Tal Ronnen Oron;Fatouma Alimirah;Albert R. Davalos;Tara E. Tracy;Li Gan;Pierre-Yves Desprez;Judith Campisi;
Journal PloS one
Year 2020
DOI
10.1371/journal.pone.0227887
URL
http://dx.plos.org/10.1371/journal.pone.0227887
Keywords
neurons astrocytes glutamate alzheimer's disease senescence sensory perception rna sequencing neuronal death

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