Astrocyte senescence promotes glutamate toxicity in cortical neurons. Academic Article uri icon

Overview

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.

publication date

  • January 16, 2020

Research

keywords

  • Alzheimer Disease
  • Astrocytes
  • Cellular Senescence
  • Neurons

Identity

PubMed Central ID

  • PMC6964973

Scopus Document Identifier

  • 85078034756

Digital Object Identifier (DOI)

  • 10.1038/nm.4010

PubMed ID

  • 31945125

Additional Document Info

volume

  • 15

issue

  • 1