Abstract
Aging is a major risk factor for many neurodegenerative disorders. A key feature of aging biology that may underlie these diseases is cellular senescence. Senescent cells accumulate in tissues with age, undergo widespread changes in gene expression, and typically demonstrate altered, pro-inflammatory profiles. Astrocyte senescence has been implicated in neurodegenerative disease, and to better understand senescence-associated changes in astrocytes, we investigated changes in their transcriptome using RNA sequencing. Senescence was induced in human fetal astrocytes by transient oxidative stress. Brain-expressed genes, including those involved in neuronal development and differentiation, were downregulated in senescent astrocytes. Remarkably, several genes indicative of astrocytic responses to injury were also downregulated, including glial fibrillary acidic protein and genes involved in the processing and presentation of antigens by major histocompatibility complex class II proteins, while pro-inflammatory genes were upregulated. Overall, our findings suggest that senescence-related changes in the function of astrocytes may impact the pathogenesis of age-related brain disorders.
Highlights
Astrocytes are the most abundant population of cells within the central nervous system (CNS) and the structural diversity and functional complexity of cortical astrocytes is a distinguishing feature of the primate brain (Oberheim et al, 2006)
In order to better understand how astrocyte senescence relates to changes in astrocyte physiology during aging, we investigated global changes in the astrocyte transcriptome using RNA Sequencing (RNA-Seq) following the induction of oxidative stress-induced senescence using H2O2
We found by a principle component analysis (PCA) that these samples were tightly clustered based on cellular treatment (Figure 1A)
Summary
Astrocytes are the most abundant population of cells within the central nervous system (CNS) and the structural diversity and functional complexity of cortical astrocytes is a distinguishing feature of the primate brain (Oberheim et al, 2006). There has been a paradigm shift toward recognizing the integral role of glial cells in the pathogenesis of age-related cognitive decline and neurodegeneration (Nagelhus et al, 2013; Phatnani and Maniatis, 2015; Pekny et al, 2016). Altered astrocyte physiology has been linked to aging and to the most common age-related neurodegenerative disorder, Alzheimer’s disease (AD), by transcriptome profiling of gene expression changes in astrocytes from aged mouse cortex (Orre et al, 2014) and in glial fibrillary acidic protein (GFAP)-positive cells isolated by laser-capture microdissection from postmortem tissues of subjects with AD (Simpson et al, 2011; Sekar et al, 2015). A greater understanding of how aging impacts astrocytes should provide new insight into age-related diseases of the brain
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