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Doxorubicin generates senescent microglia that exhibit altered proteomes, higher levels of cytokine secretion, and a decreased ability to internalize amyloid β
journal contribution
posted on 2020-08-03, 12:38 authored by Luis Costa-Marques, Adiv A Johnson, Alexandra StolzingAlexandra StolzingCellular senescence is defined by irreversible cell-cycle arrest and is an evolutionarily conserved hallmark of
aging. In this study, we generate senescent microglial cells via exposure to the chemotherapy drug doxorubicin.
Compared to control cells, doxorubicin-treated microglia exhibited an altered morphology characterized by an
enlarged cell size, a flattened appearance, and the development of prominent filaments. Senescent cells harbored
elevated levels of senescence associated-β-galactosidase, p16Ink4a, and γ-H2AX. Senescent microglia were also
less efficient at internalizing amyloid β and pHrodo bioparticles. A detailed proteomic analysis using SWATH-MS
identified 201 proteins that were significantly downregulated and 127 that were significantly upregulated in
doxorubicin-treated microglia. Proteins involved in processes such as protein synthesis, RNA damage and repair,
and protein degradation were largely downregulated while those compromising the integrity of the cell were
predominantly upregulated. Various proteins involved in proteasomal processing were among the most significantly downregulated in senescent cells. Relevant to the deleterious senescence-associated secretory phenotype,
senescent cells secreted higher levels of the inflammatory cytokines IL-6, IL-8, TNF-α, and GRO-α. Our data
suggest that symptoms of brain aging and age-related neurodegenerative disease may be partially caused by
defective phagocytosis, impaired proteasomal processing, and elevated cytokine secretion of senescent microglia
Funding
Project L1 -Effect of stem cell quality on therapy outcome - Alzheimer (Luis Marques) : EP/L015072/1
EPSRC and MRC Centre for Doctoral Training in Regenerative Medicine
Engineering and Physical Sciences Research Council
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School
- Mechanical, Electrical and Manufacturing Engineering
Published in
Experimental Cell ResearchVolume
395Issue
2Pages
112203Publisher
Elsevier BVVersion
- AM (Accepted Manuscript)
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Crown Copyright ©Publisher statement
This paper was accepted for publication in the journal Experimental Cell Research and the definitive published version is available at https://doi.org/10.1016/j.yexcr.2020.112203Acceptance date
2020-07-24Publication date
2020-07-30Copyright date
2020ISSN
0014-4827Publisher version
Language
- en
Depositor
Prof Alexandra Stolzing . Deposit date: 1 August 2020Article number
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