000150678 001__ 150678
000150678 005__ 20251017144640.0
000150678 0247_ $$2doi$$a10.1007/s11357-019-00100-3
000150678 0248_ $$2sideral$$a113130
000150678 037__ $$aART-2019-113130
000150678 041__ $$aeng
000150678 100__ $$aLye, Jed J.
000150678 245__ $$aAstrocyte senescence may drive alterations in GFAPa, CDKN2A p14ARF, and TAU3 transcript expression and contribute to cognitive decline
000150678 260__ $$c2019
000150678 5060_ $$aAccess copy available to the general public$$fUnrestricted
000150678 5203_ $$aThe 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.
000150678 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000150678 592__ $$a1.585$$b2019
000150678 593__ $$aComplementary and Alternative Medicine$$c2019$$dQ1
000150678 593__ $$aCardiology and Cardiovascular Medicine$$c2019$$dQ1
000150678 593__ $$aVeterinary (miscellaneous)$$c2019$$dQ1
000150678 593__ $$aGeriatrics and Gerontology$$c2019$$dQ1
000150678 593__ $$aAging$$c2019$$dQ2
000150678 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000150678 700__ $$0(orcid)0000-0002-5797-3909$$aLatorre, Eva$$uUniversidad de Zaragoza
000150678 700__ $$aLee, Ben P.
000150678 700__ $$aBandinelli, Stefania
000150678 700__ $$aHolley, Janet E.
000150678 700__ $$aGutowski, Nicholas J.
000150678 700__ $$aFerrucci, Luigi
000150678 700__ $$aHarries, Lorna W.
000150678 7102_ $$11002$$2050$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Biología Celular
000150678 773__ $$g41, 5 (2019), 561-573$$pGeroScience$$tGeroScience$$x2509-2715
000150678 8564_ $$s572972$$uhttps://zaguan.unizar.es/record/150678/files/texto_completo.pdf$$yVersión publicada
000150678 8564_ $$s1987129$$uhttps://zaguan.unizar.es/record/150678/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000150678 909CO $$ooai:zaguan.unizar.es:150678$$particulos$$pdriver
000150678 951__ $$a2025-10-17-14:31:32
000150678 980__ $$aARTICLE