Abstract
The accumulation of senescent cells in tissues is causally linked to the development of several age-related diseases; the removal of senescent glial cells in animal models prevents Tau accumulation and cognitive decline. Senescent cells can arise through several distinct mechanisms; one such mechanism is dysregulation of alternative splicing. In this study, we characterised the senescent cell phenotype in primary human astrocytes in terms of SA-β-Gal staining and SASP secretion, and then assessed splicing factor expression and candidate gene splicing patterns. Finally, we assessed associations between expression of dysregulated isoforms and premature cognitive decline in 197 samples from the InCHIANTI study of ageing, where expression was present in both blood and brain. We demonstrate here that senescent astrocytes secrete a modified SASP characterised by increased IL8, MMP3, MMP10, and TIMP2 but decreased IL10 levels. We identified significant changes in splicing factor expression for 10/20 splicing factors tested in senescent astrocytes compared with early passage cells, as well as dysregulation of isoform levels for 8/13 brain or senescence genes tested. Finally, associations were identified between peripheral blood GFAPα, TAU3, and CDKN2A (P14ARF) isoform levels and mild or severe cognitive decline over a 3–7-year period. Our data are suggestive that some of the features of cognitive decline may arise from dysregulated splicing of important genes in senescent brain support cells, and that defects in alternative splicing or splicing regulator expression deserve exploration as points of therapeutic intervention in the future.
Highlights
Age is a major risk factor for cognitive decline and neurodegenerative disease, as it is for most common, chronic disorders (Niccoli and Partridge, 2012)
Previous evidence has suggested that the accumulation of senescent astrocytes may drive neurodegenerative disorders (Di Malta et al, 2012) and recent work shows that clearance of senescent glial cells may prevent the accumulation of Tau aggregates and improve cognitive function in mouse models (Bussian et al, 2018, Baker and Petersen, 2018)
We hypothesised that senescent astrocytes would display differential expression of splicing regulatory factors and altered patterns of alternative splicing in vitro, and that some of these isoform changes may be detectable in peripheral blood and show statistical associations with cognitive phenotypes in human populations
Summary
Age is a major risk factor for cognitive decline and neurodegenerative disease, as it is for most common, chronic disorders (Niccoli and Partridge, 2012). We hypothesised that senescent astrocytes would display differential expression of splicing regulatory factors and altered patterns of alternative splicing in vitro, and that some of these isoform changes may be detectable in peripheral blood and show statistical associations with cognitive phenotypes in human populations. Our data are in agreement with the hypothesis that senescent astrocytes display differential expression of splicing regulatory factors and altered patterns of alternative splicing, and that some of these isoform changes may reflect those in peripheral blood Such changes may show statistical associations with cognitive phenotypes in human populations. We measured the expression levels of an a priori panel of 20 splicing factors previously associated with age, lifespan, and cellular senescence in different tissue types in our previous work (Harries et al, 2011, Holly et al, 2013, Latorre et al, 2018b). Models were adjusted for age, gender, smoking (lifetime pack-years), study site, education level, and white blood cell subtype counts (% neutrophils, monocytes, basophils, eosinophils)
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