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; Jose M Polo

doi:10.1038/s41467-021-23111-1

Transcriptional signature in microglia associated with Aβ plaque phagocytosis

Nat Commun. 2021 May 21;12(1):3015. doi: 10.1038/s41467-021-23111-1.

Authors

Alexandra Grubman^#^{1

2

3}, Xin Yi Choo^#^{4

5

6

7}, Gabriel Chew^#⁸, John F Ouyang⁸, Guizhi Sun^{4

5

6}, Nathan P Croft^{9

10}, Fernando J Rossello^{4

5

6}, Rebecca Simmons^{11

12}, Sam Buckberry^{11

12}, Dulce Vargas Landin^{11

12}, Jahnvi Pflueger^{11

12}, Teresa H Vandekolk¹³, Zehra Abay^{4

5

6}, Yichen Zhou^{4

5

6

14}, Xiaodong Liu^{4

5

6}, Joseph Chen^{4

5

6}, Michael Larcombe^{4

5

6}, John M Haynes¹³, Catriona McLean¹⁵, Sarah Williams^{4

5

6}, Siew Yeen Chai¹⁶, Trevor Wilson¹⁷, Ryan Lister^{11

12}, Colin W Pouton¹³, Anthony W Purcell^{9

10}, Owen J L Rackham⁸, Enrico Petretto¹⁸, Jose M Polo^{19

20

21}

Affiliations

¹ Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia. alexandra.grubman@monash.edu.
² Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia. alexandra.grubman@monash.edu.
³ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia. alexandra.grubman@monash.edu.
⁴ Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.
⁵ Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia.
⁶ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia.
⁷ Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
⁸ Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, 169857, Singapore, Singapore.
⁹ Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
¹⁰ Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
¹¹ ARC Center of Excellence in Plant Energy Biology, The University of Western Australia, Perth, WA, Australia.
¹² The Harry Perkins Institute of Medical Research, Perth, WA, Australia.
¹³ Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, VIC, Australia.
¹⁴ Department of Microbiology, Monash University, Clayton, VIC, Australia.
¹⁵ Victorian Brain Bank, Parkville, VIC, Australia.
¹⁶ Department of Physiology, Monash University, Clayton, VIC, Australia.
¹⁷ MHTP Medical Genomics Facility, Clayton, VIC, Australia.
¹⁸ Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, 169857, Singapore, Singapore. enrico.petretto@duke-nus.edu.sg.
¹⁹ Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia. jose.polo@monash.edu.
²⁰ Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia. jose.polo@monash.edu.
²¹ Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia. jose.polo@monash.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / metabolism*
Animals
Brain / metabolism
Disease Models, Animal
Female
Gene Expression
Gene Regulatory Networks
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Male
Mice
Microglia / metabolism*
Middle Aged
Phagocytosis / physiology*
Plaque, Amyloid / genetics
Plaque, Amyloid / metabolism*
Transcriptome

Substances

Hif1a protein, mouse
Hypoxia-Inducible Factor 1, alpha Subunit