Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology

The sustained proliferation of microglia is a key hallmark of Alzheimer’s disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased βgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aβ, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aβ pathology in AD. [Display omitted] •In Alzheimer’s-like pathology, a fraction of microglia undergo replicative senescence•Disease-associated microglia (DAM) display several features of senescence•Prevention of proliferation impairs the development of microglial senescence and DAMs•Prevention of microglial senescence leads to reduced amyloidosis and synaptic damage Hu et al. show that microglia undergo replicative senescence in a model of Alzheimer’s-like pathology. Senescence is enriched in disease-associated microglia and is caused by the accumulation of proliferative cycles. Prevention of microglial senescence leads to diminished pathology, highlighting a link of microglia with the early stages of Alzheimer’s disease.