Senescent Astrocytes May Negatively Affect the Function of Neurons

A good deal of evidence points towards cellular senescence in the supporting cells of the brain, such as astrocytes and microglia, as an important contribution to neurodegeneration, cognitive decline, and dementia. Senescent cells behave abnormally and secrete a potent mix of pro-growth, pro-inflammatory signals that are known to degrade structure and function in many different organs. Chronic inflammation in brain tissue is strongly implicated in the onset and progression of neurodegenerative conditions, and clearance of senescent cells in the brain via senolytic therapies has been shown to reverse pathology in animal models of neurodegeneration.

The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron.

In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide - stress-induced premature senescence (SIPS). Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state, represented by reduced glutathione/oxidized glutathione (GSH/GSSG), the mitochondrial morphology, and the proteins and membrane potential were determined.

Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.


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