A key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration, is suggested in research from the Buck Institute.

“This study gets to the underlying mechanisms that drive the toxicity. We have identified targets that may be of more use in drug development,"

said senior author and Buck professor Judith Campisi, Ph.D.

Glutamate Toxicity

The research[1], led by research scientist Chandani Limbad, Ph.D., found that cellular senescence in astrocytes downregulates the glutamate transporters, which are vital for glutamate homeostasis in the brain. Glutamate is one of the most important neurotransmitters in the brain; an excess of it causes neurons to repeatedly fire leading to their eventual death.

Memantine, an FDA-approved drug for Alzheimer’s disease, reduces glutamate toxicity in patients suffering from moderate to severe disease for up to a year, but evidence that the drug might slow pathology is weak.

Cellular senescence is one of the hottest topics in research on aging. Success in the Campisi lab and others around the world has given rise to companies and research projects aimed at developing either senolytics, drugs that clear senescent cells, or senomorphics, drugs that suppress the senescence-associated inflammation.

Earlier work in the Campisi lab in collaboration with the Buck Institute’s Andersen lab showed that clearing senescent cells prevented Parkinson’s in a mouse model of the disease[2].

Cellular Senescence

Campisi says that most of the research aimed at understanding the characteristics of cellular senescence involves human fibroblasts, cells in connective tissue which produce collagen and other fibers. She says this work in astrocytes should be a wake-up call to those studying Alzheimer’s disease, arguing that,

“What is commonly termed non-familial Alzheimer’s disease should probably more accurately be termed age-related dementia. If you see five spontaneous Alzheimer’s patients, all of them present differently. Some have personality changes, others don’t. Memory is affected differently in each patient; some people lose motor control, others don’t. These findings highlight aging as the biggest risk factor for almost all neurodegeneration and that is where the research should be focused."

Co-author Pierre-Yves Desprez, Ph.D., a scientific consultant in the Campisi lab, who also runs a lab at the California Pacific Medical Center Research Institute, says the research also has implications for those studying glioblastoma, a particularly aggressive form of brain cancer which happens in astrocytes.

“Cellular senescence is a double-edged sword and the current state of senescence-associated research is messy. While senescence leads to chronic inflammation which promotes cancer and neurodegeneration, it also acts as a tumor suppressor. There are many factors secreted by senescent astrocytes, we think some of them could be exploited as a way to treat glioblastoma."

The research, which involved unbiased RNA sequencing of transcripts expressed by senescent and non-senescent astrocytes, found changes in the expression of more than 5,000 genes whose functions are important in cancer, infectious diseases, and neurological diseases.

[caption id=“attachment_102260” align=“aligncenter” width=“700”]Increased neuronal death in co-cultures with SEN astrocytes dependent on glutamate. Increased neuronal death in co-cultures with SEN astrocytes dependent on glutamate.
Credit: Chandani Limbad et al, CC-BY[/caption]

Cellular senescence is a pleiotropic cell fate that prevents cancer in early life, but can also promote age-related diseases, including cancer, during aging, largely by producing pro-inflammatory SASP factors. Most of our understanding of the SASP derives from studies of human fibroblasts.

Recently, Jeon et al. showed that irradiation caused glioblastoma (GBM) cells, the most aggressive type of brain cancer, to undergo senescence. These senescent GBM cells secreted a SASP and promoted tumor cell growth. The current study shows that human primary astrocytes also undergo senescence upon irradiation and manifest some of the classical features of senescence, including a pro-inflammatory SASP.

[1] Limbad C, Oron TR, Alimirah F, Davalos AR, Tracy TE, Gan L, et al. (2020) Astrocyte senescence promotes glutamate toxicity in cortical neurons. PLoS ONE 15(1): e0227887. https://doi.org/10.1371/journal.pone.0227887

[2] Chinta, S. J., Woods, G., Demaria, M., Rane, A., Zou, Y., McQuade, A., . . . and Andersen, J. K. (2018). Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Reports, 22(4), 930–940. DOI: 10.1016/j.celrep.2017.12.092

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