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

Hu, Yanling, Fryatt, Gemma Louise, Ghorbani, Mohammadmersad, Obst, Juliane, Menassa, David, Martin estebane, Maria, Muntslag, Tim Arno Othni, Olmos alonso, Adrian, Guerrero Carrasco, Monica, Thomas, Daniel, Cragg, Mark and Gomez-Nicola, Diego (2021) Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology. Cell Reports. (doi:10.1101/2021.03.22.436174).

Abstract

The sustained proliferation of microglia is a key hallmark of Alzheimer’s 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 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. Prevention of early microglial proliferation hindered the development of senescence and DAM, impairing the accumulation of Aβ and associated neuritic damage. Overall, our results support that excessive microglial proliferation leads to the generation of senescent DAM, which contribute to early Aβ pathology in AD.

This record has no associated files available for download.

Contributors

Author: Tim Arno Othni Muntslag

Author: Mark Cragg

Author: Diego Gomez-Nicola

Download statistics