Characterizing microglial senescence: Tau as a key player

The highest risk factor for the development of neurodegenerative diseases like tauopathies is aging. Many physiological decrements underlying aging are linked to cellular senescence. Senescent cells are characterized by an irreversible growth arrest and formation of a senescence‐associated secretory phenotype (SASP), a proinflammatory secretome that modifies the cellular microenvironment and contributes to tissue deterioration. Microglia, the innate immune cells in the brain, can enter a senescent state during aging. In addition, senescent microglia have been identified in the brains of tau‐transgenic mice and patients suffering from tauopathies. While the contribution of senescent microglia to the development of tauopathies and other neurodegenerative diseases is a growing area of research, the effect of tau on microglial senescence remains elusive. Here, we exposed primary microglia to 5 and 15 nanomolar (nM) of monomeric tau for 18 h, followed by a recovery period of 48 h. Using multiple senescence markers, we found that exposure to 15 nM, but not 5 nM of tau increased levels of cell cycle arrest and a DNA damage marker, induced loss of the nuclear envelope protein lamin B1 and the histone marker H3K9me3, impaired tau clearance and migration, altered the cell morphology and resulted in formation of a SASP. Taken together, we show that exposure to tau can lead to microglial senescence. As senescent cells were shown to negatively impact tau pathologies, this suggests the presence of a vicious circle, which should be further investigated in the future. Although microglial senescence was shown to contribute to the development of tauopathies, no evidence exists for the effect of tau on microglial senescence. In the present study, we showed that exposure to monomeric tau can lead to senescence in primary microglia, illustrated by increased cell cycle arrest, DNA damage, loss of the nuclear envelope protein lamin B1 and the histone mark H3K9me3, impaired phagocytosis and migration, altered cell morphology, and formation of a SASP. As senescent cells were shown to negatively impact tau pathologies, the mechanism(s) by which monomeric tau induces senescence in microglia should be further investigated in the future (figure created with BioRender.com).