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Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity

Shoshik Amram, Tal Iram, Ekaterina Lazdon, Robert Vassar, Ittai Ben-Porath, Dan Frenkel
doi: https://doi.org/10.1101/700013
Shoshik Amram
*Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6139001, Israel
†Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6139001, Israel
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Tal Iram
*Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6139001, Israel
†Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6139001, Israel
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Ekaterina Lazdon
†Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6139001, Israel
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Robert Vassar
‡Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, 60208, USA
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Ittai Ben-Porath
§Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada (IMRIC) Hebrew University-Hadassah Medical School, Jerusalem, 9112102, Israel
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Dan Frenkel
*Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6139001, Israel
†Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6139001, Israel
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  • For correspondence: dfrenkel@tauex.tau.ac.il
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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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 12, 2019.
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Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity
Shoshik Amram, Tal Iram, Ekaterina Lazdon, Robert Vassar, Ittai Ben-Porath, Dan Frenkel
bioRxiv 700013; doi: https://doi.org/10.1101/700013
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Astrocyte senescence in an Alzheimer’s disease mouse model is mediated by TGF-β1 and results in neurotoxicity
Shoshik Amram, Tal Iram, Ekaterina Lazdon, Robert Vassar, Ittai Ben-Porath, Dan Frenkel
bioRxiv 700013; doi: https://doi.org/10.1101/700013

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