Astrocyte senescence may drive alterations in GFAP α , CDKN2A p14 ARF , and TAU3 transcript expression and contribute to cognitive decline

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 ast rocytes 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 bloodGFAP α,TAU3, andCDKN2A (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 in tervention in the future.
Source: AGE - Category: Geriatrics Source Type: research