Astrocyte senescence promotes glutamate toxicity in cortical neurons
Limbad C, Oron TR, Alimirah F, Davalos AR, Tracy TE, Gan L, Desprez PY, Campisi J. Astrocyte senescence promotes glutamate toxicity in cortical neurons. PLoS One. 2020 Jan 16;15(1):e0227887. doi: 10.1371/journal.pone.0227887. PMID: 31945125; PMCID: PMC6964973.
A study showed that glioblastoma cells undergo senescence and develop the SASP which promotes tumor growth in the brain. The authors of this paper asked whether this senescence could contribute to neurodegeneration since astrocyte senescence has been observed in AD patients.
They used X-irradiation to induce senescence in astrocytes. Since astrocytes maintain glutamate, potassium and water homeostasis, they tested how senescence would affect the expression of genes involved in these homeostatic processes. Examining the excitatory amino acid transporters 1 and 2, their qPCR showed that in senescent astrocytes these genes were downregulated.
Using RNA-seq, they checked whether senescence affected these homeostatic pathways. Senescence markers like p16INK4a mRNA were significantly increased in the senescent astrocytes and lamin B1 was decreased according to expectations since they were both known senescence markers.
Disease enrichment analysis on the differentially upregulated genes showed that they were involved in cancer, infectious disease or AD. The downregulated genes were involved in cancer and neurological disease. Using a dataset from NetWork Glia they filtered for Transporter associated astrocyte enriched genes. A gene-set enrichment analysis on this data gave a p-value of 0.08. This confirmed the downregulation of the amino acid transporters in senescent astrocytes.
Their next question was whether this downregulation affected glutamate uptake in astrocytes. Using a co-culture of neurons with senescent and non-senescent astrocytes, both with and without a 10mM solution of glutamate, they found that neurons died when cultured with glutamate and were in co-culture with senescent astrocytes. The senescent astrocytes did not take up glutamate efficiently leading to the death of co-cultured neurons.
Astrocytes are important to neuron survival and this capability is compromised when they become senescent. If astrocytes are unable maintain an appropriate level of glutamate in the brain, neurons are at risk of death from excitotoxicity. The RNA-seq also found that APOE is upregulated in senescent astrocytes which could put AD patients at greater risk of losing neurons to glutamate toxicity.