| First Author | Rueda-Carrasco J | Year | 2023 |
| Journal | EMBO J | Volume | 42 |
| Issue | 19 | Pages | e113246 |
| PubMed ID | 37575021 | Mgi Jnum | J:351099 |
| Mgi Id | MGI:7538798 | Doi | 10.15252/embj.2022113246 |
| Citation | Rueda-Carrasco J, et al. (2023) Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models. EMBO J 42(19):e113246 |
| abstractText | 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 Abeta 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 Abeta 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 Abeta-relevant context and suggest a potential beneficial role for microglia in the earliest stages of AD. |
