Transcriptional signature in microglia associated with Aβ plaque phagocytosis

Date

2021

Authors

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.

Editors

Advisors

Journal Title

Journal ISSN

Volume Title

Type:

Journal article

Citation

Nature Communications, 2021; 12(1):3015-1-3015-22

Statement of Responsibility

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

Conference Name

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.

School/Discipline

Dissertation Note

Provenance

Description

Access Status

Rights

© 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/.

License

Call number

Persistent link to this record