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

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 SmithVeronique E Miron, Ragnhildur Thóra Káradóttir, Giles E Hardingham, Christopher M Henstridge, Paul M Brennan, Barry W McColl, Tara L Spires-Jones

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	101175
Pages (from-to)	1-23
Number of pages	23
Journal	Cell Reports Medicine
Volume	4
Issue number	9
Early online date	30 Aug 2023
DOIs	https://doi.org/10.1016/j.xcrm.2023.101175
Publication status	Published - 19 Sept 2023

Keywords / Materials (for Non-textual outputs)

Alzheimer’s disease
astrocytes
microglia
synapses
synapse loss
MFGE8

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10.1016/j.xcrm.2023.101175

PIIS2666379123003282Final published version, 5.95 MBLicence: CC BY

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer’s disease via MFG-E8
Spires-Jones, T. (Creator), Edinburgh DataShare, 27 Jul 2023
DOI: 10.7488/ds/7492, https://doi.org/10.1101/795930
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Tzioras, M., Daniels, M. J. D., Davies, C., Baxter, P., King, D., McKay, S., Varga, B., Popovic, K., Hernandez, M., Stevenson, A. J., Barrington, J., Drinkwater, E., Borella, J., Holloway, R. K., Tulloch, J., Moss, J., Latta, C., Kandasamy, J., Sokol, D., ... Spires-Jones, T. L. (2023). Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8. Cell Reports Medicine, 4(9), 1-23. Article 101175. https://doi.org/10.1016/j.xcrm.2023.101175

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

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{\textquoteright}s disease, astrocytes, microglia, synapses, synapse loss, MFGE8",

author = "Makis Tzioras and Daniels, {Michael J D} and Caitlin Davies and Paul Baxter and Declan King and Sean McKay and Balazs Varga and Karla Popovic and Madison Hernandez and Stevenson, {Anna J} and Jack Barrington and Elizabeth Drinkwater and Julia Borella and Holloway, {Rebecca K} and Jane Tulloch and Jonathan Moss and Clare Latta and Jothy Kandasamy and Drahoslav Sokol and Colin Smith and Miron, {Veronique E} and K{\'a}rad{\'o}ttir, {Ragnhildur Th{\'o}ra} and Hardingham, {Giles E} and Henstridge, {Christopher M} and Brennan, {Paul M} and McColl, {Barry W} and Spires-Jones, {Tara L}",

year = "2023",

month = sep,

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doi = "10.1016/j.xcrm.2023.101175",

language = "English",

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journal = "Cell Reports Medicine",

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Tzioras, M, Daniels, MJD, Davies, C, Baxter, P , King, D, McKay, S, Varga, B, Popovic, K, Hernandez, M, Stevenson, AJ, Barrington, J, Drinkwater, E, Borella, J, Holloway, RK, Tulloch, J , Moss, J, Latta, C, Kandasamy, J, Sokol, D, Smith, C , Miron, VE, Káradóttir, RT, Hardingham, GE, Henstridge, CM, Brennan, PM , McColl, BW & Spires-Jones, TL 2023, 'Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8', Cell Reports Medicine, vol. 4, no. 9, 101175, pp. 1-23. https://doi.org/10.1016/j.xcrm.2023.101175

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

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

U2 - 10.1016/j.xcrm.2023.101175

DO - 10.1016/j.xcrm.2023.101175

M3 - Article

C2 - 37652017

SN - 2666-3791

VL - 4

SP - 1

EP - 23

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 9

M1 - 101175

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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

Cite this