Astrocyte senescence promotes glutamate toxicity in cortical neurons


Autoři: Chandani Limbad aff001;  Tal Ronnen Oron aff001;  Fatouma Alimirah aff001;  Albert R. Davalos aff001;  Tara E. Tracy aff001;  Li Gan aff003;  Pierre-Yves Desprez aff001;  Judith Campisi aff001
Působiště autorů: Buck Institute for Research on Aging, Novato, California, United States of America aff001;  Comparative Biochemistry Graduate Program, University of California, Berkeley, California, United States of America aff002;  Gladstone Institute of Neurological Disease, San Francisco, California, United States of America aff003;  Department of Neurology, Weill Institute of Neuroscience, University of California, San Francisco, California, United States of America aff004;  California Pacific Medical Center, San Francisco, California, United States of America aff005;  Lawrence Berkeley National Laboratory, Berkeley, California, United States of America aff006
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227887

Souhrn

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.

Klíčová slova:

Alzheimer's disease – Astrocytes – Gene expression – Glutamate – Neuronal death – Neurons – RNA sequencing – Senescence


Zdroje

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