
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.31.606944
preprint
1
Article
Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer’s disease mouse models
Sokolova Dimitra http://orcid.org/0000-0001-8925-5154

Ghansah Shari Addington
Puletti Francesca
Georgiades Tatiana
De Schepper Sebastiaan http://orcid.org/0000-0003-0640-2417

Zheng Yongjing
Crowley Gerard http://orcid.org/0000-0003-0436-1332

Wu Ling
Rueda-Carrasco Javier http://orcid.org/0000-0002-9280-6612

Koutsiouroumpa Angeliki
Muckett Philip
Freeman Oliver J. http://orcid.org/0000-0003-4009-282X

Khakh Baljit S. http://orcid.org/0000-0002-0939-1218

Hong Soyon http://orcid.org/0000-0002-5744-4871

01 9 2024
2024.08.31.606944https://creativecommons.org/licenses/by-nd/4.0/ This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
http://biorxiv.org/lookup/doi/10.1101/2024.08.31.606944
nihpp-2024.08.31.606944.pdf
Summary

Region-specific synapse loss is an early pathological hallmark in Alzheimer’s disease (AD). Emerging data in mice and humans highlight microglia, the brain-resident macrophages, as cellular mediators of synapse loss; however, the upstream modulators of microglia-synapse engulfment remain elusive. Here, we report a distinct subset of astrocytes, which are glial cells essential for maintaining synapse homeostasis, appearing in a region-specific manner with age and amyloidosis at onset of synapse loss. These astrocytes are distinguished by their peri-synaptic processes which are ‘bulbous’ in morphology, contain accumulated p62-immunoreactive bodies, and have reduced territorial domains, resulting in a decrease of astrocyte-synapse coverage. Using integrated in vitro and in vivo approaches, we show that astrocytes upregulate and secrete phagocytic modulator, milk fat globule-EGF factor 8 (MFG-E8), which is sufficient and necessary for promoting microglia-synapse engulfment in their local milieu. Finally, we show that knocking down Mfge8 specifically from astrocytes using a viral CRISPR-saCas9 system prevents microglia-synapse engulfment and ameliorates synapse loss in two independent amyloidosis mouse models of AD. Altogether, our findings highlight astrocyte-microglia crosstalk in determining synapse fate in amyloid models and nominate astrocytic MFGE8 as a potential target to ameliorate synapse loss during the earliest stages of AD.
==== Body
pmc
