Cellular Senescence as the Key Intermediate in Tau-Mediated Neurodegeneration

Neuroinflammation is thought to play a key role in the progression of neurodegenerative disease such as Alzheimer's disease (AD). Given the apparent nexus of inflammatory disease with the secretory-associated senescence phenotype (SASP) of cellular senescence, two reports found that tau-mediated neurodegeneration involves induction of senescence in astrocytes, microglia, and possibly even neurons. Elimination of senescent cells by pharmacologically induced genetic ablation or by senolytic drugs blocks progression of mutant human tau-mediated neurodegeneration in mice. This work suggests a working hypothesis through which tau activation leads to senescence and then tau propagation throughout the brain is supported by, and neurotoxicity is caused by, SASP, forming a pathological positive feedback loop. Although preliminary, these data suggest that the development of senolytics for AD and other tauopathies, especially early disease, and possibly senomodulatory drugs for later stage neurodegenerative disease may prove fruitful.