TY - JOUR
T1 - Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8
AU - Tzioras, Makis
AU - Daniels, Michael J. D.
AU - Davies, Caitlin
AU - Baxter, Paul
AU - King, Declan
AU - McKay, Sean
AU - Varga, Balazs
AU - Popovic, Karla
AU - Hernandez, Madison
AU - Stevenson, Anna J.
AU - Barrington, Jack
AU - Drinkwater, Elizabeth
AU - Borella, Julia
AU - Holloway, Rebecca K.
AU - Tulloch, Jane
AU - Moss, Jonathan
AU - Latta, Clare
AU - Kandasamy, Jothy
AU - Sokol, Drahoslav
AU - Smith, Colin
AU - Miron, Veronique E.
AU - Káradóttir, Ragnhildur Thóra
AU - Hardingham, Giles E.
AU - Henstridge, Christopher M.
AU - Brennan, Paul M.
AU - McColl, Barry W.
AU - Spires-Jones, Tara L.
N1 - Funding Information:
This work was funded by the UK Dementia Research Institute, which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK, the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 681181), Alzheimer’s Research UK, and the Scottish Government Chief Scientist Office (ARUK SPG2013-1), a Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund, MND Scotland, and Alzheimer’s Society. Electron micrographs were obtained at the Roslin Institute 3D Electron Microscopy Facility (funded by BBSRC Institute Strategic Program support).
Copyright:
© 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2023/9/19
Y1 - 2023/9/19
N2 - 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.
AB - 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.
KW - Alzheimer’s disease
KW - astrocytes
KW - microglia
KW - synapses
KW - synapse loss
KW - MFGE8
UR - http://www.scopus.com/inward/record.url?scp=85171543907&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2023.101175
DO - 10.1016/j.xcrm.2023.101175
M3 - Article
C2 - 37652017
SN - 2666-3791
VL - 4
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 9
M1 - 101175
ER -
