Do senescent cells play a role in Alzheimer’s disease?

Abstract

AbstractBackgroundCellular senescence, the irreversible arrest of the cell cycle, is a common occurrence in ageing. Astrocytes have been shown to demonstrate a senescent phenotype, which is increased in ageing, and in Alzheimer’s disease (AD) (as evidenced by p16INK4a expression). Recently, a causal link was established between p16INK4a expression and hyperphosphorylated tau (HPT) pathology in the MAPTP301SPS19 mouse model of tauopathy, where treatment with a senolytic agent removed senescent p16INK4a positive astrocytes, prevented aggregation of HPT, and preserved cognitive function, suggesting senescent astrocytes may play a role in HPT deposition observed in AD. However, data in human post‐mortem tissue from AD cases (inclusive of Aβ pathology) is lacking.MethodFrontal cortex (BA9) from 10 AD and 10 control cases were double immunolabelled for GFAP and p16INK4a. A mean number of p16INK4a positive astrocytes (identified by the presence of co‐localisations) was determined at 6 regions of interest across each section. HPT and Aβ were quantified by percentage area of immunopositivity in the same region.ResultAD cases had significantly more p16INK4a positive astrocytes compared to controls (p<0.05). We observed a positive association between number of p16INK4a positive astrocytes and HPT load in AD cases (p<0.05). No association was observed between the mean number of p16INK4a positive astrocytes and Aβ load.ConclusionWe found a positive association was found between p16INK4a positive astrocytes and HPT. This area of research warrants further investigation to determine whether the development of senolytic therapies are a viable option for the treatment of AD and other tauopathies.