Astrocyte senescence may drive alterations in GFAPα, CDKN2A p14ARF, and TAU3 transcript expression and contribute to cognitive decline.
dc.contributor.author | Lye, JJ | |
dc.contributor.author | Latorre, E | |
dc.contributor.author | Lee, BP | |
dc.contributor.author | Bandinelli, S | |
dc.contributor.author | Holley, JE | |
dc.contributor.author | Gutowski, NJ | |
dc.contributor.author | Ferrucci, L | |
dc.contributor.author | Harries, LW | |
dc.date.accessioned | 2019-11-20T16:28:21Z | |
dc.date.issued | 2019-10-25 | |
dc.description.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. | en_GB |
dc.description.sponsorship | Dunhill Medical Trust | en_GB |
dc.description.sponsorship | National Institute of Health (NIH) | en_GB |
dc.identifier.citation | Published online 25 October 2019 | en_GB |
dc.identifier.doi | 10.1007/s11357-019-00100-3 | |
dc.identifier.grantnumber | R386/1114 | en_GB |
dc.identifier.grantnumber | National institute on Ageing Intramural Research Program | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/39643 | |
dc.language.iso | en | en_GB |
dc.publisher | Springer International Publishing | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/31654269 | en_GB |
dc.rights | © The Author(s) 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. | en_GB |
dc.subject | Alternative splicing | en_GB |
dc.subject | Gene expression | en_GB |
dc.subject | Neurodegenerative disease | en_GB |
dc.subject | Senescence | en_GB |
dc.title | Astrocyte senescence may drive alterations in GFAPα, CDKN2A p14ARF, and TAU3 transcript expression and contribute to cognitive decline. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2019-11-20T16:28:21Z | |
dc.identifier.issn | 2509-2715 | |
exeter.place-of-publication | Switzerland | en_GB |
dc.description | This is the final published version. Available from Springer International Publishing via the DOI in this record. | en_GB |
dc.identifier.journal | Geroscience | en_GB |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2019-09-10 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2019-09-10 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2019-11-20T16:25:52Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2019-11-20T16:28:24Z | |
refterms.panel | A | en_GB |
Files in this item
This item appears in the following Collection(s)
Except where otherwise noted, this item's licence is described as © The Author(s) 2019
Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.