Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8

Makis Tzioras; Michael J D Daniels; Caitlin Davies; Paul Baxter; Declan King; Sean McKay; Balazs Varga; Karla Popovic; Madison Hernandez; Anna J Stevenson; Jack Barrington; Elizabeth Drinkwater; Julia Borella; Rebecca K Holloway; Jane Tulloch; Jonathan Moss; Clare Latta; Jothy Kandasamy; Drahoslav Sokol; Colin Smith; Veronique E Miron; Ragnhildur Thóra Káradóttir; Giles E Hardingham; Christopher M Henstridge; Paul M Brennan; Barry W McColl; Tara L Spires-Jones

doi:10.1016/j.xcrm.2023.101175

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8

Cell Rep Med. 2023 Sep 19;4(9):101175. doi: 10.1016/j.xcrm.2023.101175. Epub 2023 Aug 30.

Authors

Makis Tzioras¹, Michael J D Daniels¹, Caitlin Davies¹, Paul Baxter¹, Declan King¹, Sean McKay¹, Balazs Varga², Karla Popovic¹, Madison Hernandez¹, Anna J Stevenson¹, Jack Barrington¹, Elizabeth Drinkwater¹, Julia Borella¹, Rebecca K Holloway³, Jane Tulloch¹, Jonathan Moss⁴, Clare Latta¹, Jothy Kandasamy⁵, Drahoslav Sokol⁵, Colin Smith⁶, Veronique E Miron⁷, Ragnhildur Thóra Káradóttir², Giles E Hardingham¹, Christopher M Henstridge⁸, Paul M Brennan⁹, Barry W McColl¹⁰, Tara L Spires-Jones¹¹

Affiliations

¹ UK Dementia Research Institute, the University of Edinburgh, Edinburgh EH8 9JZ, UK; Centre for Discovery Brain Sciences, the University of Edinburgh, Edinburgh EH8 9JZ, UK.
² Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK.
³ MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh EH16 4TJ, UK.
⁴ MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh EH16 4TJ, UK; The Roslin Institute, the Royal (Dick) School of Veterinary Studies, the University of Edinburgh, Edinburgh EH25 9RG, UK.
⁵ Department of Clinical Neurosciences, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.
⁶ Centre for Clinical Brain Sciences, the University of Edinburgh, Edinburgh EH16 4SB, UK.
⁷ UK Dementia Research Institute, the University of Edinburgh, Edinburgh EH8 9JZ, UK; MRC Centre for Reproductive Health, the University of Edinburgh, Edinburgh EH16 4TJ, UK; Barlo Multiple Sclerosis Centre at St. Michael's Hospital, Keenan Research Centre for Biomedical Science, Toronto, ON M5B 1T8, Canada.
⁸ Division of Systems Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
⁹ Department of Clinical Neurosciences, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK; Centre for Clinical Brain Sciences, the University of Edinburgh, Edinburgh EH16 4SB, UK.
¹⁰ UK Dementia Research Institute, the University of Edinburgh, Edinburgh EH8 9JZ, UK; Centre for Discovery Brain Sciences, the University of Edinburgh, Edinburgh EH8 9JZ, UK. Electronic address: barry.mccoll@ed.ac.uk.
¹¹ UK Dementia Research Institute, the University of Edinburgh, Edinburgh EH8 9JZ, UK; Centre for Discovery Brain Sciences, the University of Edinburgh, Edinburgh EH8 9JZ, UK. Electronic address: tara.spires-jones@ed.ac.uk.

Abstract

Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared with non-disease controls, and that proximity to amyloid-β plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting interactions of MFG-E8 rescues the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells at least in part via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation.

Keywords: Alzheimer’s disease; MFGE8; astrocytes; microglia; synapse loss; synapses.

Publication types

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

MeSH terms

Alzheimer Disease*
Animals
Astrocytes
Eating
Humans
Mice
Microglia*
Synapses

Substances

MFGE8 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding