Exploring potential glial senescence signatures in Alzheimer’s disease

Abstract

Background: Glial cells’ ability to maintain homeostasis in the brain and regulate neuroinflammation is altered in Alzheimer’s disease. Senescent glia – glia with irreversible cell cycle arrest, resistance to apoptosis, and pro-inflammatory cytokine secretion – are associated with exacerbated amyloid-β and tau pathology. GLB1 is widely associated with predicting glial senescence in ageing. Aims, objectives, and hypothesis: Using imaging mass cytometry data, we aimed to quantify microglia and astrocytes and identify their potential senescence signatures. We hypothesized that a glial senescence signature, predicted by GLB1 co-expression, exists in AD. Methods: Using in-house-generated imaging mass cytometry data from the mid-temporal gyrus of post-mortem brain tissue, cell counts of Iba-1-positive microglia and GFAP-positive astrocytes were determined in AD and control cases. The expression of senescence markers, and the co-expression of GLB1 in senescence-expressing glia were investigated. Independent sample t-tests with an FDR correction were used for between-group comparisons (or the Mann–Whitney U test if data failed the normality test). Results: There was no significant difference between groups in Iba-1-positive microglia and GFAP-positive astrocyte counts. Iba-1-positive microglia did not show a senescence signature, while GFAP-positive astrocytes showed increased senescence expression in p21, γ-H2AX, and GLB1. Cells positive for GLB1 and other senescence markers only showed a significant increase in GFAP-positive astrocytes. Conclusions and future directions: Reactive astrocytes were associated with a GLB1- associated senescence signature in Alzheimer’s disease, whereas microglia were not. This senescence-like phenotype may suggest the vulnerability of reactive glia to oxidative stress and DNA damage. This work highlights the possibility of targeting GLB1-expressing reactive astrocytes for senescent cell-eliminating drugs – senolytics.