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Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models

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. Green open access

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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.

Type: Article
Title: Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.2022113246
Publisher version: https://doi.org/10.15252/embj.2022113246
Language: English
Additional information: © 2023 The Authors. Published under the terms of the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
Keywords: Abeta oligomers, Alzheimer's disease, microglia, pruning, synapses
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10175587
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