Transcriptional signature in microglia associated with Aβ plaque phagocytosis

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 H. Vandekolk, Zehra Abay, Yichen Zhou, Xiaodong Liu, Joseph Chen, Michael Larcombe, John M. Haynes, Catriona McLean, Sarah Williams, Siew Yeen Chai, Trevor Wilson, Ryan Lister, Colin W. Pouton, Anthony W. Purcell, Owen J. L. Rackham, Enrico Petretto () and Jose M. Polo ()
Additional contact information
Alexandra Grubman: Monash University
Xin Yi Choo: Monash University
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
Nathan P. Croft: Monash University
Fernando J. Rossello: Monash University
Rebecca Simmons: ARC Center of Excellence in Plant Energy Biology, The University of Western Australia
Sam Buckberry: ARC Center of Excellence in Plant Energy Biology, The University of Western Australia
Dulce Vargas Landin: ARC Center of Excellence in Plant Energy Biology, The University of Western Australia
Jahnvi Pflueger: ARC Center of Excellence in Plant Energy Biology, The University of Western Australia
Teresa H. Vandekolk: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus)
Zehra Abay: Monash University
Yichen Zhou: Monash University
Xiaodong Liu: Monash University
Joseph Chen: Monash University
Michael Larcombe: Monash University
John M. Haynes: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus)
Catriona McLean: Victorian Brain Bank
Sarah Williams: 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
Colin W. Pouton: Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus)
Anthony W. Purcell: 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

Nature Communications, 2021, vol. 12, issue 1, 1-22

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23111-1

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