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Microglia Detect Externalized Phosphatidylserine on Synapses for Elimination via TREM2 in Alzheimer’s Disease Models

View ORCID ProfileJavier Rueda-Carrasco, View ORCID ProfileDimitra Sokolova, View ORCID ProfileSang-Eun Lee, View ORCID ProfileThomas Childs, Natália Jurčáková, View ORCID ProfileSebastiaan De Schepper, Judy Z. Ge, Joanne I. Lachica, View ORCID ProfileChristina E. Toomey, View ORCID ProfileOliver J. Freeman, View ORCID ProfileJohn Hardy, View ORCID ProfileBeth Stevens, View ORCID ProfileTammaryn Lashley, View ORCID ProfileSunghoe Chang, View ORCID ProfileSoyon Hong
doi: https://doi.org/10.1101/2022.04.04.486424
Javier Rueda-Carrasco
1UK Dementia Research Institute, Institute of Neurology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
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Dimitra Sokolova
1UK Dementia Research Institute, Institute of Neurology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
2Neuroscience BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
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Sang-Eun Lee
1UK Dementia Research Institute, Institute of Neurology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
3Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 01030, South Korea
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Thomas Childs
1UK Dementia Research Institute, Institute of Neurology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
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Natália Jurčáková
1UK Dementia Research Institute, Institute of Neurology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
4Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
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Sebastiaan De Schepper
1UK Dementia Research Institute, Institute of Neurology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
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Judy Z. Ge
1UK Dementia Research Institute, Institute of Neurology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
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Joanne I. Lachica
5The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, WC1N 3BG United Kingdom
6Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
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Christina E. Toomey
5The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, WC1N 3BG United Kingdom
6Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
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Oliver J. Freeman
2Neuroscience BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
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John Hardy
1UK Dementia Research Institute, Institute of Neurology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
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Beth Stevens
7F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Massachusetts 02115, United States of America; Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA., USA
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Tammaryn Lashley
5The Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, WC1N 3BG United Kingdom
8Department of Neurodegenerative diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom
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Sunghoe Chang
3Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 01030, South Korea
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Soyon Hong
1UK Dementia Research Institute, Institute of Neurology, University College London, Gower Street, London, WC1E 6BT, United Kingdom
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  • For correspondence: soyon.hong@ucl.ac.uk
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Abstract

Genetic studies implicate phagocytosis pathways in microglia to be a major Alzheimer’s disease (AD)-associated process. Microglia phagocytose synapses in AD mouse models, suggesting a role for microglia in region-specific synapse loss, a pathological hallmark of AD. However, whether specific synapses are targeted for elimination, and if so, how, remains to be elucidated. Here, we show that synapses externalize phosphatidylserine (PtdSer) upon challenge by β-amyloid oligomers, which are then selectively engulfed by microglia. Mechanistically, we find that Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is critical for microglia to sense and preferentially engulf AD synapses. In brains of mice and humans, TREM2 dysfunction leads to exacerbation of apoptotic synapses. Our work altogether suggests a fundamental role for microglia as brain-resident macrophages to remove damaged synapses in AD. We provide mechanistic insight into how TREM2 variants associated with increased risk of developing AD may contribute to defective microglia-synapse function.

One-Sentence summary Microglia selectively engulf synapses in Alzheimer-like mouse brains via PtdSer-TREM2 signaling.

Competing Interest Statement

OJF is employed by AstraZeneca. The following patents have been granted or applied for: PCT/2015/010288, US14/988387 and EP14822330 (SH).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 05, 2022.
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Microglia Detect Externalized Phosphatidylserine on Synapses for Elimination via TREM2 in Alzheimer’s Disease Models
Javier Rueda-Carrasco, Dimitra Sokolova, Sang-Eun Lee, Thomas Childs, Natália Jurčáková, Sebastiaan De Schepper, Judy Z. Ge, Joanne I. Lachica, Christina E. Toomey, Oliver J. Freeman, John Hardy, Beth Stevens, Tammaryn Lashley, Sunghoe Chang, Soyon Hong
bioRxiv 2022.04.04.486424; doi: https://doi.org/10.1101/2022.04.04.486424
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Microglia Detect Externalized Phosphatidylserine on Synapses for Elimination via TREM2 in Alzheimer’s Disease Models
Javier Rueda-Carrasco, Dimitra Sokolova, Sang-Eun Lee, Thomas Childs, Natália Jurčáková, Sebastiaan De Schepper, Judy Z. Ge, Joanne I. Lachica, Christina E. Toomey, Oliver J. Freeman, John Hardy, Beth Stevens, Tammaryn Lashley, Sunghoe Chang, Soyon Hong
bioRxiv 2022.04.04.486424; doi: https://doi.org/10.1101/2022.04.04.486424

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