<scp>HIV</scp> and drug abuse mediate astrocyte senescence in a β‐catenin‐dependent manner leading to neuronal toxicity

Yu, Chunjiang; Narasipura, Srinivas D.; Richards, Maureen; Hu, Xiu‐Ti; Yamamoto, Bryan K.; Al‐Harthi, Lena

doi:10.1111/acel.12593

Cited by 47 publications

(32 citation statements)

References 45 publications

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“…Given that premature senescence from HAART drugs and HIV proteins has been linked to comorbidities in non‐CNS cell types (Beaupere et al, ; Nacarelli, Azar, & Sell, ), astrocyte senescence in response to these stimuli could be a contributor to HAND. Indeed, a very recent study demonstrated that human astrocytes infected with an HIV plasmid underwent premature senescence (Yu et al, ). Conditioned media from these senescent astrocytes induced neuronal apoptosis suggesting that senescent astrocytes could have an adverse effect on the CNS microenvironment in the context of HIV and HAND.…”

Section: Neurodegenerative Disease and Astrocyte Senescencementioning

confidence: 99%

Astrocyte senescence: Evidence and significance

2019

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Astrocytes participate in numerous aspects of central nervous system (CNS) physiology ranging from ion balance to metabolism, and disruption of their physiological roles can therefore be a contributor to CNS dysfunction and pathology. Cellular senescence, one of the mechanisms of aging, has been proposed as a central component of the age dependency of neurodegenerative disorders. Cumulative evidence supports an integral role of astrocytes in the initiation and progression of neurodegenerative disease and cognitive decline with aging. The loss of astrocyte function or the gain of neuroinflammatory function as a result of cellular senescence could have profound implications for the aging brain and neurodegenerative disorders, and we propose the term “astrosenescence” to describe this phenotype. This review summarizes the current evidence pertaining to astrocyte senescence from early evidence, in vitro characterization and relationship to age‐related neurodegenerative disease. We discuss the significance of targeting senescent astrocytes as a novel approach toward therapies for age‐associated neurodegenerative disease.

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Section: Neurodegenerative Disease and Astrocyte Senescencementioning

confidence: 99%

Astrocyte senescence: Evidence and significance

2019

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“…By secreting SASP factors, the SASP can trigger immune surveillance of senescent cells ( Xue et al, 2007 ), enforce cell cycle arrest ( Acosta et al, 2008 ; Bartek et al, 2008 ), and alter tissue microenvironments ( Tchkonia et al, 2013 ). Evidence also suggest that the SASP can induce paracrine senescence in normal cells ( Kuilman et al, 2008 ; Yu et al, 2017 ) via the SASP proteins IGFBP7 ( Wajapeyee et al, 2008 ) and IL-6 ( Acosta et al, 2013 ), which goes further in explaining how the SASP alter tissue microenvironments ( González-Puertos et al, 2015 ). The NISIM, by integrating the SASP, could perhaps help elucidate some of the antecedent aspects regarding the induction of age-related pathologies ( Figures 2 , 3 ).…”

Section: Applying the Model: Neurodegenerative Disease And Cancermentioning

confidence: 99%

The Neuro-Immuno-Senescence Integrative Model (NISIM) on the Negative Association Between Parasympathetic Activity and Cellular Senescence

2018

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There is evidence that accumulated senescent cells drive age-related pathologies, but the antecedents to the cellular stressors that induce senescence remain poorly understood. Previous research suggests that there is a relationship between shorter telomere length, an antecedent to cellular senescence, and psychological stress. Existing models do not sufficiently account for the specific pathways from which psychological stress regulation is converted into production of reactive oxygen species. We propose the neuro-immuno-senescence integrative model (NISIM) suggesting how vagally mediated heart rate variability (HRV) might be related to cellular senescence. Prefrontally modulated, and vagally mediated cortical influences on the autonomic nervous system, expressed as HRV, affects the immune system by adrenergic stimulation and cholinergic inhibition of cytokine production in macrophages and neutrophils. Previous findings indicate that low HRV is associated with increased production of the pro-inflammatory cytokines IL-6 and TNF-α. IL-6 and TNF-α can activate the NFκB pathway, increasing production of reactive oxygen species that can cause DNA damage. Vagally mediated HRV has been related to an individual’s ability to regulate stress, and is lower in people with shorter telomeres. Based on these previous findings, the NISIM suggest that the main pathway from psychological stress to individual differences in oxidative telomere damage originates in the neuroanatomical components that modulate HRV, and culminates in the cytokine-induced activation of NFκB. Accumulated senescent cells in the brain is hypothesized to promote age-related neurodegenerative disease, and previous reports suggest an association between low HRV and onset of Alzheimer’s and Parkinson’s disease. Accumulating senescent cells in peripheral tissues secreting senescence-associated secretory phenotype factors can alter tissue structure and function which can induce cancer and promote tumor growth and metastasis in old age, and previous research suggested that ability to regulate psychological stress has a negative association with cancer onset. We therefore conclude that the NISIM can account for a large proportion of the individual differences in the psychological stress-related antecedents to cellular senescence, and suggest that it can be useful in providing a dynamic framework for understanding the pathways by which psychological stress induce pathologies in old age.

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“…Astrocytes are highly specialized cells in the CNS with well-established immune and non-immune functions including glutamate uptake, maintenance of the blood brain barrier (BBB), and secretion of immune modulators, including IL-6 [20,[39][40][41][42][43][44][45]. We previously reported that astrocytes have robust expression of the Wnt/β-catenin signaling pathway and its disrupting, in response to inflammation and or viral infection, leads to dysregulation of key functions of astrocytes including induction of astrocyte senescence [41,46]. IL-6 is a hallmark cytokine associated with the senescence associated secretory phenotype (SASP), a collection of cytokines and other secretory factors secreted under cellular senescence [47][48][49][50][51].…”

Section: Introductionmentioning

confidence: 99%

β-Catenin and TCFs/LEF signaling discordantly regulate IL-6 expression in astrocytes

et al. 2020

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Background: The Wnt/β-catenin signaling pathway is a prolific regulator of cell-to-cell communication and gene expression. Canonical Wnt/β-catenin signaling involves partnering of β-catenin with members of the TCF/LEF family of transcription factors (TCF1, TCF3, TCF4, LEF1) to regulate gene expression. IL-6 is a key cytokine involved in inflammation and is particularly a hallmark of inflammation in the brain. Astrocytes, specialized glial cells in the brain, secrete IL-6. How astrocytes regulate IL-6 expression is not entirely clear, although in other cells NFκB and C/ EBP pathways play a role. We evaluated here the interface between β-catenin, TCFs/LEF and C/EBP and NF-κB in relation to IL-6 gene regulation in astrocytes. Methods: We performed molecular loss and/or gain of function studies of β-catenin, TCF/LEF, NFκB, and C/EBP to assess IL-6 regulation in human astrocytes. Specifically, siRNA mediated target gene knockdown, cDNA over expression of target gene, and pharmacological agents for regulation of target proteins were used. IL-6 levels was evaluated by real time quantitative PCR and ELISA. We also cloned the IL-6 promoter under a firefly luciferase reporter and used bioinformatics, site directed mutagenesis, and chromatin immunoprecipitation to probe the interaction between β-catenin/TCFs/LEFs and IL-6 promoter activity. Results: β-catenin binds to TCF/LEF to inhibits IL-6 while TCFs/LEF induce IL-6 transcription through interaction with ATF-2/SMADs. β-catenin independent of TCFs/LEF positively regulates C/EBP and NF-κB, which in turn activate IL-6 expression. The IL-6 promoter has two putative regions for TCFs/LEF binding, a proximal site located at-91 nt and a distal site at-948 nt from the transcription start site, both required for TCF/LEF induction of IL-6 independent of β-catenin. Conclusion: IL-6 regulation in human astrocytes engages a discordant interaction between β-catenin and TCF/LEF. These findings are intriguing given that no role for β-catenin nor TCFs/LEF to date is associated with IL-6 regulation and suggest that β-catenin expression in astrocytes is a critical regulator of anti-inflammatory responses and its disruption can potentially mediate persistent neuroinflammation.

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HIV and drug abuse mediate astrocyte senescence in a β‐catenin‐dependent manner leading to neuronal toxicity

Cited by 47 publications

References 45 publications

Astrocyte senescence: Evidence and significance

Astrocyte senescence: Evidence and significance

The Neuro-Immuno-Senescence Integrative Model (NISIM) on the Negative Association Between Parasympathetic Activity and Cellular Senescence

β-Catenin and TCFs/LEF signaling discordantly regulate IL-6 expression in astrocytes

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