Telomere-driven senescence accelerates tau pathology, neuroinflammation and neurodegeneration in a tauopathy mouse model

The connection between aging and neurodegenerative pathologies like Alzheimer's disease (AD) has long been recognized, with senescent brain cells building up in the brains of AD patients. A causal link has been established between senescence and AD-related tauopathy, but the mechanisms underlying these pathological changes remain largely unknown. To unravel the precise role of cellular senescence in tau-mediated neuropathology, we crossed the Terc knockout (Terc^-/-) mouse model of telomere-induced senescence with the P301S tauopathy model (PS19 line). Using brain sections and protein extracts, an array of biochemical and molecular techniques was applied to investigate the expression of tau-related neuropathological features within a senescent context. Our results showed that the brains of 6- and 9-month-old Terc^-/- mice exhibit significant telomere attrition and signs of cellular senescence. Additionally, we found evidence that the introduction of a senescent phenotype in a tauopathy mouse model results in increased tau phosphorylation at key residues, particularly in the hippocampus. Over time, this leads to enhanced tau truncation and aggregation, accompanied by exacerbated astrocyte and microglial activation, as well as selective neuronal loss in vulnerable brain regions. Overall, these findings place senescence as a key upstream regulator of tau pathology and tau-related neurodegeneration, suggesting that targeting senescent cells and their detrimental effects may offer promising therapeutic strategies for AD and other related tauopathies.