Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence.

Xin Yan, Christina Georgopoulou, Hang-Mao Lee, Ala Ahrari, Jenny Russ, Vijay Chandrasekar, Tim Ducksch, Giuliano Crispatzu, Valentina Talevi, Liang Qiao, Shobhit Agrawal, Sophie Crux, Andrew W Daman, Lena Wischhof, Miriam Stork, Margit Zweyer, Emma Dorotea Zanfi, Manon Chevallot-Beroux, Yunxiao Li, Elena De-Domenico, Dina Hüsson, Lorenzo Bonaguro, Yuanfang Li, Jonas Schulte-Schrepping, Qingyi Liang, Ketty Kessler, Dan Ehninger, Shahin Rafii, Jiankai Luo, Andreas Hermann, Annett Halle, Ying Liu, Elvira Mass, Melania Capasso, Hiroki Kato, Joachim L Schultze, Pierluigi Nicotera, Daniele Bano, Steven Zvi Josefowicz, Martin Fuhrmann, Thomas Ulas, Marc Beyer, Juntang Lin, Monique M B Breteler, N Ahmad Aziz, Paolo Salomoni

Nuclear Function Group, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. [email protected]. · pubmed

Paper

Abstract

Aging-associated loss of chromatin compaction is linked to derepression of retrotransposable elements (RTEs) in mouse and human tissues. Whether such RTE transcription contributes to the microglia activation that is common in aged brains is unknown. Here, we show that DAXX, a histone chaperone and RTE repressor, is downregulated during aging, preserves microglia homeostasis and inhibits cellular senescence. Loss of Daxx in young-adult microglia drives a reactive phenotype marked by chromatin decompaction at RTEs, loss of homeostatic markers, cell cycle re-entry and behavioral changes. This state leads to DNA damage and microglial depletion, followed by replacement with DAXX-deficient/Apoe

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Research summary

The paper claims that age-related downregulation of the histone chaperone DAXX leads to endogenous retrovirus derepression, driving microglial inflammation and senescence. This is relevant because it identifies a specific epigenetic mechanism (chromatin decompaction via DAXX loss) as a root cause of brain aging and neuroinflammation, offering a potential target for interventions aimed at preserving microglial homeostasis and delaying aging-associated cognitive decline.

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