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In a recent study, a group of researchers from Hebrew University-Hadassah Medical School, Feinberg School of Medicine, and Tel Aviv University examined astrocytes in mice and found that these cells exhibited a senescent phenotype that led to neurodegeneration and neurotoxicity [1].

Age-dependent increase in senescent astrocytes adjacent to Aβ plaques

Cellular senescence, discovered in 1961 by Leonard Hayflick and Paul Moorhead, is a state in which cells no longer perform their functions, instead emitting harmful chemicals that turn other cells senescent.. These cells are caused primarily by telomere shortening and DNA damage, they are known to contribute to many diseases, and this is not the first study that links them to neurodegeneration.

Astrocytes are the most abundant type of glial cells, which support neurons, in the central nervous system. These star-shaped cells provide neurons with a nutrient called lactate and regulate the transmission of electrical impulses in the brain.

The researchers studied 5XFAD mice, which have Alzheimer’s disease-linked mutations, and found that senescent astrocytes tended to form and exhibit senescent phenotypes next to amyloid-β plaques.

Senescent astrocytes secrete interleukin-6, which is a pro-inflammatory cytokine associated with Alzheimer’s disease. Its secretion was reduced in this study with the inhibition of nuclear factor-kappa light-chain-enhancer of activated B cells, which is a crucial transcription factor produced in response to several types of stresses and the secretion of pro-inflammatory cytokines.

Additionally, senescent cells exhibited an increase in the induction of the TGF-β1-SMAD2/3 pathway, the inhibition of which results in a decrease in cellular senescence.

Abstract

Alterations in astrocyte function such as a pro-inflammatory phenotype are associated with Alzheimer’s disease (AD). We had shown impairments in the ability of aged astrocytes isolated from 5xFAD mice to clear and uptake amyloid-β (Aβ) as well as to support neuronal growth. Senescent cells accumulate with age and exhibit a senescence-associated secretory phenotype, which includes secretion of pro-inflammatory cytokines. In this study, we predicted that with age, astrocytes in 5xFAD mice would exhibit a cellular senescence phenotype that could promote neurodegeneration. We found an age-dependent increase in senescent astrocytes adjacent to Aβ plaques in 5xFAD mice. Inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells reduced interelukin-6 secretion by senescent astrocytes and resulted in improved neuronal support. Moreover, senescent astrocytes exhibited an increase in the induction of the TGF-β1-SMAD2/3 pathway, and inhibition of this pathway resulted in a reduction of cellular senescence. We also discovered that soluble Aβ42 induced astrocyte senescence in young naïve mice in a SMAD2/3-dependent manner. Our results suggest an important role of astrocyte senescence in AD and its role in mediating the neurotoxicity properties of astrocytes in AD and related neurodegenerative diseases.

Conclusion

Alzheimer’s is a debilitating neurological disease that promises to become an epidemic by 2050. By pinpointing the causes, we could eventually find more efficient and usable solutions for this disease.

More and more research about AD is emerging, and people are finding new ways to diagnose it, such as through retinal scans [2], and biotechnology companies are also seeking new ways to potentially cure it, such as telomerase therapy.

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Literature

[1] Amram, S., Iram, T., Lazdon, E., Vassar, R., Ben-Porath, I., & Frenkel, D. (2019). Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity. BioRxiv. doi:10.1101/700013

[2] Kerbage, C., Sadowsky, C. H., Jennings, D., Cagle, G. D., & Hartung, P. D. (2013). Alzheimer’s Disease Diagnosis by Detecting Exogenous Fluorescent Signal of Ligand Bound to Beta Amyloid in the Lens of Human Eye: An Exploratory Study. Frontiers in Neurology, 4. doi:10.3389/fneur.2013.00062

About the author
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Nina Khera

Nina Khera is a 13-year-old longevity & genomics researcher. She specializes in senescent cells & their eradication and is working on a project to find biomarkers, markers, and targeted treatments for senescent cells. Nina spoke at Connect I.T., will speak at Collision, and aspires to be a human longevity researcher working with senescent cells.
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