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

Hu, Y.; Fryatt, G. L.; Ghorbani, M.; Obst, J.; Menassa, D. A.; Martin-Estebane, M.; Muntslag, T. A. O.; Olmos-Alonso, A.; Guerrero-Carrasco, M.; Thomas, D. L.; Cragg, M. S.; Gomez-Nicola, D.

doi:10.1101/2021.03.22.436174

bioRxiv · 10.1101/2021.03.22.436174

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

Hu, Y.·Fryatt, G. L.·Ghorbani, M.·Obst, J.·Menassa, D. A.·Martin-Estebane, M.·Muntslag, T. A. O.·Olmos-Alonso, A.·Guerrero-Carrasco, M.·Thomas, D. L.·Cragg, M. S.·Gomez-Nicola, D.

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Abstract

The sustained proliferation of microglia is a key hallmark of Alzheimers disease (AD), accelerating its progression. Here, we sought to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesising that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We found that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterised by increased {beta}gal 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. Prevention of early microglial proliferation hindered the development of senescence and DAM, impairing the accumulation of A{beta} and associated neuritic damage. Overall, our results support that excessive microglial proliferation leads to the generation of senescent DAM, which contribute to early A{beta} pathology in AD.

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Hu, Y., Fryatt, G. L., Ghorbani, M., Obst, J., Menassa, D. A., Martin-Estebane, M., Muntslag, T. A. O., Olmos-Alonso, A., Guerrero-Carrasco, M., Thomas, D. L., Cragg, M. S., Gomez-Nicola, D.. 2021-03-22. Replicative senescence dictates the emergence of disease-associated microglia and contributes to Abeta pathology. https://doi.org/10.1101/2021.03.22.436174

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