Grubman, A.Choo, X.Y.Chew, G.Ouyang, J.F.Sun, G.Croft, N.P.Rossello, F.J.Simmons, R.Buckberry, S.Landin, D.V.Pflueger, J.Vandekolk, T.H.Abay, Z.Zhou, Y.Liu, X.Chen, J.Larcombe, M.Haynes, J.M.McLean, C.Williams, S.et al.2021-12-212021-12-212021Nature Communications, 2021; 12(1):3015-1-3015-222041-17232041-1723https://hdl.handle.net/2440/133831The role of microglia cells in Alzheimer’s disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4⁺) and non-containing (XO4⁻) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4⁺ microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4⁺ microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4⁻ microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4⁺ microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together, these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.en© The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Amyloid plaqueBrainMicrogliaAnimalsHumansMiceAlzheimer DiseaseDisease Models, AnimalPhagocytosisGene ExpressionAgedAged, 80 and overMiddle AgedFemaleMaleHypoxia-Inducible Factor 1, alpha SubunitGene Regulatory NetworksPlaque, AmyloidTranscriptomeJournal article10.1038/s41467-021-23111-12021-12-21594156Polo, J.M. [0000-0002-2531-778X]