Cited by 183Telomeres, Telomerase, and SenescenceNeuroinflammation and Neurodegeneration MechanismsGenetics, Aging, and Longevity in Model Organisms

Astrocyte senescence promotes glutamate toxicity in cortical neurons

Open access
Limbad, Chandani, Oron, Tal Ronnen, Alimirah, Fatouma, Davalos, Albert R., Tracy, Tara E., Gan, Li, Desprez, Pierre-Yves, Campisi, Judith·2020·PLOS ONE

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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Crossref · 10.1371/journal.pone.0227887

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  • Primary human astrocytes exposed to X-rays exhibit increased expression of senescence-associated proteins (p16INK4a and Hp1γ) and cytokines associated with SASP, such as IL-1β and IL-6.

    “Furthermore, primary human astrocytes exposed to X-rays exhibit increased expression of senescence-associated proteins (p16INK4a and Hp1γ) and cytokines associated with SASP, such as IL-1β and IL-6.294–296”

    From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [295]

    The Results section, “Irradiation induces senescence and a SASP in human primary astrocytes” (page unavailable), reports increased p16INK4a mRNA and IL-6 expression and secretion after X-irradiation. It does not report increased p16INK4a protein or identify increased HP1γ or IL-1β in these astrocytes. (LLM, conf=0.90)

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Authors
Limbad, C., Oron, T. R., Alimirah, F., Davalos, A. R., Tracy, T. E., Gan, L., Desprez, P.-Y., & Campisi, J.
Affiliations
  • Buck Institute for Research on Aging (US)
  • Gladstone Institutes (US)
Corresponding author
Campisi, Judith
Venue
PLOS ONE
Published
2020-01-16
Volume
15
Issue
1
Pages
e0227887
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2999084078
Cited by
183
References
63
Citations by year
2026: 18 · 2025: 26 · 2024: 30 · 2023: 26 · 2022: 36 · 2021: 36 · 2020: 11
FWCI
16.39
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
National Institute on Aging (AG009909, AG017242)
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
astrocyte senescence, cellular senescence, glutamate excitotoxicity, excitotoxicity, glutamate transporters, potassium transporters, glutamate homeostasis, neurodegeneration, Alzheimer's disease, senescence-associated secretory phenotype, X-ray irradiation, cortical neurons, neuronal cell death
MeSH terms
Alzheimer Disease, Astrocytes, Brain, Gene Expression Regulation, Humans, Nerve Degeneration, Neurons, X-Rays, Cellular Senescence, Glutamic Acid, Amino Acid Transport System X-AG, Cell Cycle Checkpoints, Primary Cell Culture

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