Glial Cell Senescence Increases with Age in Alzheimer's Mouse Model

Alzheimer's Disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and the accumulation of amyloid plaques and tau tangles. Cellular senescence, a state where cells stop dividing and secrete inflammatory factors, is increasingly recognized as a contributor to aging and various diseases, including neurodegeneration. While senescence is implicated in AD pathology, the cell type-specific and age-dependent dynamics of senescence markers in glial cells within AD models remain underexplored, representing a critical knowledge gap.

The study revealed a significant age-dependent increase in the expression of senescence markers p16, p21, and p53 specifically within glial cells of the AppNL-G-F mouse model. Astrocytes showed a particularly pronounced increase, with p16 expression elevated by ~3.5-fold and p21 by ~2.8-fold in aged AD mice compared to young AD mice (p<0.001). Microglial cells also exhibited elevated senescence, with p53 levels increasing by ~2.1-fold in aged AD mice (p<0.01). These increases were significantly more pronounced in the AD model compared to age-matched wild-type controls, suggesting that AD pathology accelerates glial senescence. > The most striking finding was that aged AppNL-G-F mice displayed a 40-50% higher burden of senescent glial cells compared to age-matched wild-type controls, indicating a strong link between AD pathology and glial senescence.