Rueda-Carrasco, Javier;
Sokolova, Dimitra;
Lee, Sang-Eun;
Childs, Thomas;
Jurčáková, Natália;
Crowley, Gerard;
De Schepper, Sebastiaan;
... Hong, Soyon; + view all
(2023)
Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models.
The EMBO Journal
, Article e113246. 10.15252/embj.2022113246.
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Rueda-Carrasco_Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models_VoR.pdf - Published Version Download (3MB) | Preview |
Abstract
Neuronal hyperactivity is a key feature of early stages of Alzheimer's disease (AD). Genetic studies in AD support that microglia act as potential cellular drivers of disease risk, but the molecular determinants of microglia-synapse engulfment associated with neuronal hyperactivity in AD are unclear. Here, using super-resolution microscopy, 3D-live imaging of co-cultures, and in vivo imaging of lipids in genetic models, we found that spines become hyperactive upon Aβ oligomer stimulation and externalize phosphatidylserine (ePtdSer), a canonical "eat-me" signal. These apoptotic-like spines are targeted by microglia for engulfment via TREM2 leading to amelioration of Aβ oligomer-induced synaptic hyperactivity. We also show the in vivo relevance of ePtdSer-TREM2 signaling in microglia-synapse engulfment in the hAPP NL-F knock-in mouse model of AD. Higher levels of apoptotic-like synapses in mice as well as humans that carry TREM2 loss-of-function variants were also observed. Our work supports that microglia remove hyperactive ePtdSer+ synapses in Aβ-relevant context and suggest a potential beneficial role for microglia in the earliest stages of AD.
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