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Transcriptional signature in microglia associated with Aβ plaque phagocytosis

Author

Listed:
  • Alexandra Grubman

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University)

  • Xin Yi Choo

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University
    The University of Melbourne)

  • Gabriel Chew

    (Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School)

  • John F. Ouyang

    (Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School)

  • Guizhi Sun

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University)

  • Nathan P. Croft

    (Monash University
    Infection and Immunity Program, Biomedicine Discovery Institute, Monash University)

  • Fernando J. Rossello

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University)

  • Rebecca Simmons

    (ARC Center of Excellence in Plant Energy Biology, The University of Western Australia
    The Harry Perkins Institute of Medical Research)

  • Sam Buckberry

    (ARC Center of Excellence in Plant Energy Biology, The University of Western Australia
    The Harry Perkins Institute of Medical Research)

  • Dulce Vargas Landin

    (ARC Center of Excellence in Plant Energy Biology, The University of Western Australia
    The Harry Perkins Institute of Medical Research)

  • Jahnvi Pflueger

    (ARC Center of Excellence in Plant Energy Biology, The University of Western Australia
    The Harry Perkins Institute of Medical Research)

  • Teresa H. Vandekolk

    (Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus))

  • Zehra Abay

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University)

  • Yichen Zhou

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University
    Department of Microbiology, Monash University)

  • Xiaodong Liu

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University)

  • Joseph Chen

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University)

  • Michael Larcombe

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University)

  • John M. Haynes

    (Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus))

  • Catriona McLean

    (Victorian Brain Bank)

  • Sarah Williams

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University)

  • Siew Yeen Chai

    (Monash University)

  • Trevor Wilson

    (MHTP Medical Genomics Facility)

  • Ryan Lister

    (ARC Center of Excellence in Plant Energy Biology, The University of Western Australia
    The Harry Perkins Institute of Medical Research)

  • Colin W. Pouton

    (Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus))

  • Anthony W. Purcell

    (Monash University
    Infection and Immunity Program, Biomedicine Discovery Institute, Monash University)

  • Owen J. L. Rackham

    (Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School)

  • Enrico Petretto

    (Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School)

  • Jose M. Polo

    (Monash University
    Development and Stem Cells Program, Monash Biomedicine Discovery Institute
    Australian Regenerative Medicine Institute, Monash University)

Abstract

The 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.

Suggested Citation

  • Alexandra Grubman & Xin Yi Choo & Gabriel Chew & John F. Ouyang & Guizhi Sun & Nathan P. Croft & Fernando J. Rossello & Rebecca Simmons & Sam Buckberry & Dulce Vargas Landin & Jahnvi Pflueger & Teresa, 2021. "Transcriptional signature in microglia associated with Aβ plaque phagocytosis," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23111-1
    DOI: 10.1038/s41467-021-23111-1
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    Cited by:

    1. Mengyan Hu & Tiemei Li & Xiaomeng Ma & Sanxin Liu & Chunyi Li & Zhenchao Huang & Yinyao Lin & Ruizhen Wu & Shisi Wang & Danli Lu & Tingting Lu & Xuejiao Men & Shishi Shen & Huipeng Huang & Yuxin Liu &, 2023. "Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Tomalika R. Ullah & Matt D. Johansen & Katherine R. Balka & Rebecca L. Ambrose & Linden J. Gearing & James Roest & Julian P. Vivian & Sunil Sapkota & W. Samantha N. Jayasekara & Daniel S. Wenholz & Vi, 2023. "Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Juan F. Quintana & Praveena Chandrasegaran & Matthew C. Sinton & Emma M. Briggs & Thomas D. Otto & Rhiannon Heslop & Calum Bentley-Abbot & Colin Loney & Luis de Lecea & Neil A. Mabbott & Annette MacLe, 2022. "Single cell and spatial transcriptomic analyses reveal microglia-plasma cell crosstalk in the brain during Trypanosoma brucei infection," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Caroline Wasén & Leah C. Beauchamp & Julia Vincentini & Shuqi Li & Danielle S. LeServe & Christian Gauthier & Juliana R. Lopes & Thais G. Moreira & Millicent N. Ekwudo & Zhuoran Yin & Patrick da Silva, 2024. "Bacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer’s disease mouse models," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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