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Title: Astrocyte senescence promotes glutamate toxicity in cortical neurons

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.

Authors:
 [1];  [2];  [2];  [2];  [3];  [4]; ORCiD logo [5];  [6];  [7]
  1. Buck Inst. for Research on Aging, Novato, CA (United States); Univ. of California, Berkeley, CA (United States)
  2. Buck Inst. for Research on Aging, Novato, CA (United States)
  3. 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)
  4. Gladstone Inst. of Neurological Disease, San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States)
  5. Buck Inst. for Research on Aging, Novato, CA (United States); California Pacific Medical Center, San Francisco, CA (United States)
  6. Buck Inst. for Research on Aging, Novato, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  7. National Center for Geriatrics and Gerontology, Obu (Japan)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH)
OSTI Identifier:
1603600
Grant/Contract Number:  
AC02-05CH11231; AG009909; AG017242
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 15; Journal Issue: 1; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; astocytes; glutamate; neurons; Alzheimer's disease; neuronal death; senescence; RNA sequencing; gene expression

Citation Formats

Limbad, Chandani, Oron, Tal Ronnen, Alimirah, Fatouma, Davalos, Albert R., Tracy, Tara E., Gan, Li, Desprez, Pierre-Yves, Campisi, Judith, and Iijima, Koichi M. Astrocyte senescence promotes glutamate toxicity in cortical neurons. United States: N. p., 2020. Web. https://doi.org/10.1371/journal.pone.0227887.
Limbad, Chandani, Oron, Tal Ronnen, Alimirah, Fatouma, Davalos, Albert R., Tracy, Tara E., Gan, Li, Desprez, Pierre-Yves, Campisi, Judith, & Iijima, Koichi M. Astrocyte senescence promotes glutamate toxicity in cortical neurons. United States. https://doi.org/10.1371/journal.pone.0227887
Limbad, Chandani, Oron, Tal Ronnen, Alimirah, Fatouma, Davalos, Albert R., Tracy, Tara E., Gan, Li, Desprez, Pierre-Yves, Campisi, Judith, and Iijima, Koichi M. Thu . "Astrocyte senescence promotes glutamate toxicity in cortical neurons". United States. https://doi.org/10.1371/journal.pone.0227887. https://www.osti.gov/servlets/purl/1603600.
@article{osti_1603600,
title = {Astrocyte senescence promotes glutamate toxicity in cortical neurons},
author = {Limbad, Chandani and Oron, Tal Ronnen and Alimirah, Fatouma and Davalos, Albert R. and Tracy, Tara E. and Gan, Li and Desprez, Pierre-Yves and Campisi, Judith and Iijima, Koichi M.},
abstractNote = {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.},
doi = {10.1371/journal.pone.0227887},
journal = {PLoS ONE},
number = 1,
volume = 15,
place = {United States},
year = {2020},
month = {1}
}

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