Contribution of senescent and reactive astrocytes on central nervous system inflammaging

López-Teros, Michel; Alarcón-Aguilar, Adriana; López‐Díazguerrero, Norma Edith; Luna–López, Armando; Königsberg, Mina

doi:10.1007/s10522-022-09952-3

Cited by 19 publications

(14 citation statements)

References 67 publications

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“… 55 – 57 Aging, a major risk factor for glaucoma, leads to chronic low-grade inflammation of the CNS. 58 In Spp1 KO astrocytes, production of inflammatory mediators is chronically elevated, even at a young age, whereas the neurotrophic factors are down-regulated. This may shift the balance of protective and detrimental functions into the neurodegenerative direction and expedite natural age-related ganglion cell loss and increase susceptibility to glaucoma.…”

Section: Discussionmentioning

confidence: 99%

Secreted phosphoprotein 1 slows neurodegeneration and rescues visual function in mouse models of aging and glaucoma

Li¹,

Jakobs²

2022

Cell Reports

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Section: Discussionmentioning

confidence: 99%

Secreted phosphoprotein 1 slows neurodegeneration and rescues visual function in mouse models of aging and glaucoma

Li¹,

Jakobs²

2022

Cell Reports

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“…Transient local cytokine secretion might promote the brain's recovery after injury, but long-term upregulation might result in damage (76). IL-6 expression is expected to be found in a senescence-associated secretory profile (SASP), a phenotypic shift leading to premature or stress-induced cellular senescence (119)(120)(121). An irreversible cell cycle arrest is a major characteristic of cellular senescence (49, 50).…”

Section: Gene Expression Of Astrocytesmentioning

confidence: 99%

“…which is not further enhanced by in vitro exposure to ionizing radiation. TP53 was reported to regulate cellular senescence in astrocytes induced by ionizing radiation exposure (119). The absence of a decided TP53 gene expression signature (including e.g., the expression of Cdkn1a-p21) in the RNA sequencing data after X-rays exposure might explain why the radiation response of primary astrocytes was so reluctant.…”

Section: Figurementioning

confidence: 99%

“…Another possibility is that a senescent phenotype is present because of high basal expression of Cdkn1a and Cdkn2a, the major mediators of senescence-associated proliferation arrest (121), that did not further increase after treatment. In vivo, cellular senescence describes a state in which astrocytes do not replicate but remain alive in the tissue, producing pro-inflammatory and neurotoxic factors, and contributing to CNS damage (119,125). Such aging of astrocytes was associated with a smaller pool of synaptic vesicles in co-cultured neurons and decreased neuroprotective capacity (126, 127).…”

Section: Figurementioning

confidence: 99%

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Unraveling astrocyte behavior in the space brain: Radiation response of primary astrocytes

Roggan

Kronenberg

Wollert

et al. 2023

Front. Public Health

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IntroductionExposure to space conditions during crewed long-term exploration missions can cause several health risks for astronauts. Space radiation, isolation and microgravity are major limiting factors. The role of astrocytes in cognitive disturbances by space radiation is unknown. Astrocytes' response toward low linear energy transfer (LET) X-rays and high-LET carbon (12C) and iron (56Fe) ions was compared to reveal possible effects of space-relevant high-LET radiation. Since astronauts are exposed to ionizing radiation and microgravity during space missions, the effect of simulated microgravity on DNA damage induction and repair was investigated.MethodsPrimary murine cortical astrocytes were irradiated with different doses of X-rays, 12C and 56Fe ions at the heavy ion accelerator GSI. DNA damage and repair (γH2AX, 53BP1), cell proliferation (Ki-67), astrocytes' reactivity (GFAP) and NF-κB pathway activation (p65) were analyzed by immunofluorescence microscopy. Cell cycle progression was investigated by flow cytometry of DNA content. Gene expression changes after exposure to X- rays were investigated by mRNA-sequencing. RT-qPCR for several genes of interest was performed with RNA from X-rays- and heavy-ion-irradiated astrocytes: Cdkn1a, Cdkn2a, Gfap, Tnf, Il1β, Il6, and Tgfβ1. Levels of the pro inflammatory cytokine IL-6 were determined using ELISA. DNA damage response was investigated after exposure to X-rays followed by incubation on a 2D clinostat to simulate the conditions of microgravity.ResultsAstrocytes showed distinct responses toward the three different radiation qualities. Induction of radiation-induced DNA double strand breaks (DSBs) and the respective repair was dose-, LET- and time-dependent. Simulated microgravity had no significant influence on DNA DSB repair. Proliferation and cell cycle progression was not affected by radiation qualities examined in this study. Astrocytes expressed IL-6 and GFAP with constitutive NF-κB activity independent of radiation exposure. mRNA sequencing of X-irradiated astrocytes revealed downregulation of 66 genes involved in DNA damage response and repair, mitosis, proliferation and cell cycle regulation.DiscussionIn conclusion, primary murine astrocytes are DNA repair proficient irrespective of radiation quality. Only minor gene expression changes were observed after X-ray exposure and reactivity was not induced. Co-culture of astrocytes with microglial cells, brain organoids or organotypic brain slice culture experiments might reveal whether astrocytes show a more pronounced radiation response in more complex network architectures in the presence of other neuronal cell types.

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“…Inflammaging in the brain is characterized by increased neuroinflammation of astrocytes (4,5) and microglia (6,7), aberrant infiltration of immune cells into the parenchyma (8), loss of synapses (9,10), and impaired cognition (6,11,12). Inflammaging in the periphery (13,14) and within the brain (15)(16)(17) is detectable before the onset of disease symptoms, and failure to resolve this chronic inflammation has been hypothesized to be a major contributor to aging-related cognitive decline.…”

Section: Introductionmentioning

confidence: 99%

Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function

Adams,

Rege,

Liu

et al. 2023

Sci. Adv.

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Leukotrienes, a class of inflammatory bioactive lipids, are well studied in the periphery, but less is known of their importance in the brain. We identified that the enzyme leukotriene A4 hydrolase (LTA4H) is expressed in healthy mouse neurons, and inhibition of LTA4H in aged mice improves hippocampal dependent memory. Single-cell nuclear RNA sequencing of hippocampal neurons after inhibition reveals major changes to genes important for synaptic organization, structure, and activity. We propose that LTA4H inhibition may act to improve cognition by directly inhibiting the enzymatic activity in neurons, leading to improved synaptic function. In addition, LTA4H plasma levels are increased in both aging and Alzheimer’s disease and correlated with cognitive impairment. These results identify a role for LTA4H in the brain, and we propose that LTA4H inhibition may be a promising therapeutic strategy to treat cognitive decline in aging related diseases.

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Contribution of senescent and reactive astrocytes on central nervous system inflammaging

Cited by 19 publications

References 67 publications

Secreted phosphoprotein 1 slows neurodegeneration and rescues visual function in mouse models of aging and glaucoma

Secreted phosphoprotein 1 slows neurodegeneration and rescues visual function in mouse models of aging and glaucoma

Unraveling astrocyte behavior in the space brain: Radiation response of primary astrocytes

Leukotriene A4 hydrolase inhibition improves age-related cognitive decline via modulation of synaptic function

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