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

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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

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. Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8. Cell reports. Medicine. 2023 Sep 19;4(9):101175

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PMID: 37652017

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