Alternative splicing and its contribution to cognitive decline in the ageing brain

Abstract

Premature cognitive decline is a feature of age-related pathological processes, often associated with neurodegenerative disorders. Part of the systemic ageing process is the accumulation of senescent cells in tissues around the body, including the brain. Cellular senescence contributes to the systemic inflammation which comes with ageing and disrupts several cellular regulatory mechanisms. Alternative splicing is one of these processes. Here, we first characterise the inflammatory component or senescence associated secretory phenotype and the splicing dysregulation within astrocytes. We then observe and quantify the effects of this on the alternative splicing of essential transcripts related to astrocyte function. Finally, we assess the correlation between observable levels of splicing perturbation in peripheral whole blood and the progression of cognitive decline in a population study. As a result, we identify potential biomarkers for the cognitive decline associated with dementia and other neurodegenerative disorders.