Astrocyte senescence promotes glutamate toxicity in cortical neurons

Limbad, Chandani; Oron, Tal Ronnen; Alimirah, Fatouma; Davalos, Albert R.; Tracy, Tara E.; Gan, Li; Desprez, Pierre-Yves; Campisi, Judith; Iijima, Koichi M.

doi:10.1371/journal.pone.0227887

Astrocyte senescence promotes glutamate toxicity in cortical neurons

Journal Article · Thu Jan 16 00:00:00 EST 2020 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0227887· OSTI ID:1603600

Limbad, Chandani ^[1]; Oron, Tal Ronnen ^[2]; Alimirah, Fatouma ^[2]; Davalos, Albert R. ^[2]; Tracy, Tara E. ^[3]; Gan, Li ^[4]; ^[5]; Campisi, Judith ^[6]; Iijima, Koichi M. ^[7]

Buck Inst. for Research on Aging, Novato, CA (United States); Univ. of California, Berkeley, CA (United States)
Buck Inst. for Research on Aging, Novato, CA (United States)
Buck Inst. for Research on Aging, Novato, CA (United States); Gladstone Inst. of Neurological Disease, San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States)
Gladstone Inst. of Neurological Disease, San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States)
Buck Inst. for Research on Aging, Novato, CA (United States); California Pacific Medical Center, San Francisco, CA (United States)
Buck Inst. for Research on Aging, Novato, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
National Center for Geriatrics and Gerontology, Obu (Japan)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1603600

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 1 Vol. 15; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Alzheimer's disease
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astocytes
gene expression
glutamate
neuronal death
neurons
senescence

Astrocyte senescence promotes glutamate toxicity in cortical neurons

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