Ageing of Microglia
Ageing is a strong risk factor for ALS (Pandya and Patani, 2019). Emerging evidence has suggested that the microglial transcriptome undergoes vast changes during normal ageing. Recent studies have reported an increase in inflammatory pathways in microglia during ageing in mice (Clarke et al., 2018; Hammond et al., 2019; Pan et al., 2020). Increased activation of inflammatory pathways has also been observed in human brains across several different regions (Soreq et al., 2017). In this study, changes in gene expression across different regions of the human brain upon ageing were mostly associated with microglia and astrocytes rather than neurons. While mouse and human microglia share many genes, upon ageing human microglia have been shown to undergo more dramatic changes in gene expression (Galatro et al., 2017). Together, these studies show that ageing of microglia has been correlated with an increased inflammatory response, which may partially account for the correlation between ALS and ageing.
It has been reported that microglia increasingly display markers of ageing-associated cellular senescence during disease progression in mSOD1 mice including p16INK4a, increased β-galactosidase activity and the loss of nuclear Lamin B1 (Trias et al., 2019). Cellular senescence is an adaptive mechanism that is activated in damaged cells in order to maintain their survival, prevent harmful proliferation and coordinate tissue remodelling (Muñoz-Espín and Serrano, 2014). A direct link between senescence and neurodegeneration has been reported in the MAPTP301SPS19 mouse model of Alzheimer's disease as increased p16INK4a and β-galactosidase activity in microglia and astrocytes was observed in the cortex and hippocampus during disease progression and removal of p16INK4a positive senescent cells reduced neurodegeneration and cognitive decline (Bussian et al., 2018). However, both p16INK4a and β-galactosidase activity have been shown to be reversible in stimulated macrophages and therefore may be distinct from typical cellular senescence pathways (Hall et al., 2017). It remains unknown whether these markers can be used as biomarkers or are actionable drug targets for microglia in ALS.
Brain. 2020;143(12):3526-3539. © 2020 Oxford University Press