DNA damage drives a unique, Alzheimer’s disease-relevant senescent state in neurons

Senescent cells have also been shown to accumulate in the brain with age, yet the mechanisms linking AD pathology to the accumulation of senescent cells in the brain remain unclear. Here, we demonstrate that DNA damage in patient-derived directly induced neurons (iNs) drives a senescent-like cell state with relevance to AD.

DNA damage-induced senescent iNs show significant transcriptional concordance with human AD neurons and a weighted gene co-expression network analysis (WGCNA) uncovers candidate regulators associated with the senescent-like state in neurons. Direct comparison of iNs to the original patient fibroblasts reveals striking cell-type specific senescence signatures following DNA damage. iNs adopt a p21-associated senescent-like state characterized by a senescence-associated secretory phenotype (SASP) and predicted activation of NF-κꞴ1.