Systematic profiling reveals distinct senescence signatures and regulators across human brain cell types.

Cellular senescence contributes to age-related neurodegeneration, yet its manifestation varies across brain cell types and senescence-inducing stressors. Here, we investigated senescence hallmarks in five human brain cell lines - astrocytes, endothelial cells, microglia, oligodendrocytes, and dopaminergic-like neurons - using chronic 5-Bromodeoxyuridine treatment and validated our findings in primary cells and alternative toxin-induced models. Principal component analysis and transcriptional network inference identified both common and cell-type-specific senescence-associated transcriptional regulators (SATRs). Functional studies of TFAP4, a key SATR, revealed its role in modulating senescence phenotypes in a cell-type-dependent manner, with decreased TFAP4 expression observed in Parkinson's Disease patient tissue and in vivo models. These results delineate distinct senescence profiles across brain cell types and highlight transcriptional regulators that may underlie senescence heterogeneity, offering insights into targeted therapeutic strategies for neurodegenerative diseases.