https://doi.org/10.1016/j.celrep.2021.109228
Article
Replicative senescence dictates the emergence of disease-associated microglia and contributes to A¥â pathologyHighlights
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In Alzheimer¡¯s-like pathology, a fraction of microglia undergo replicative senescence
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Disease-associated microglia (DAM) display several features of senescence
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Prevention of proliferation impairs the development of microglial senescence and DAMs
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Prevention of microglial senescence leads to reduced amyloidosis and synaptic damage
Summary
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 ¥âgal 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 A¥â, 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 A¥â pathology in AD.