We are analyzing https://link.springer.com/article/10.1007/s11357-019-00100-3.

Title:
Astrocyte senescence may drive alterations in GFAPα, CDKN2A p14ARF, and TAU3 transcript expression and contribute to cognitive decline | GeroScience
Description:
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.
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Keywords {🔍}

splicing, pubmed, expression, senescent, cells, article, decline, cognitive, astrocytes, google, scholar, senescence, cell, cas, human, levels, tau, central, latorre, alternative, factor, passage, ageing, blood, genes, disease, study, brain, demonstrated, isoforms, severe, cellular, transcripts, isoform, mild, table, gfapα, cdkna, parf, early, data, astrocyte, transcript, harries, primary, sasp, patterns, function, factors, peripheral,

Topics {✒️}

mini-mental state examination article download pdf mini-mental state exam existing transcriptomic profiles alternative pre-mrna splicing full size table multiple age-related phenotypes tau-dependent pathology tokarsky-amiel age-related splicing factor transcripts demonstrating senescence-related 3r/4r isoform ratios human-tau mouse model sa-β-gal staining cross-sectional population study privacy choices/manage cookies senescent glial cells open access license post-mortem tissue lysosomal storage disorder context-dependent control blood-based isoform production primary human astrocytes human primary astrocytes senescent endothelial cells multiple cell types 4r splice variants exeter medical school tau isoform imbalance cell subtype populations frontotemporal lobar dementia human tau protein alternative mrna splicing intramural research program alternatively spliced regulator ethics declarations declarations late passage cells increased inflammatory microenvironment conditioned media derived tau mis-splicing clinical research branch display differential expression late passage astrocytes full access espindola sl inflammatory increases evident dunhill medical trust astrocyte cell kinetics encodes tau protein splicing regulatory factors

Schema {🗺️}

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         headline:Astrocyte senescence may drive alterations in GFAPα, CDKN2A p14ARF, and TAU3 transcript expression and contribute to cognitive decline
         description: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.
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      headline:Astrocyte senescence may drive alterations in GFAPα, CDKN2A p14ARF, and TAU3 transcript expression and contribute to cognitive decline
      description: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.
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         Alternative splicing
         Senescence
         Gene expression
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         Geriatrics/Gerontology
         Molecular Medicine
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      name:University of Exeter Medical School & Neurology Department, Royal Devon & Exeter Hospital, Exeter, UK
      name:National Institute on Aging, Clinical Research Branch, Harbor Hospital, Baltimore, USA
      name:Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, UK

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