Your browser doesn't support javascript.
loading
Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models.
Rueda-Carrasco, Javier; Sokolova, Dimitra; Lee, Sang-Eun; Childs, Thomas; Jurcáková, Natália; Crowley, Gerard; De Schepper, Sebastiaan; Ge, Judy Z; Lachica, Joanne I; Toomey, Christina E; Freeman, Oliver J; Hardy, John; Barnes, Samuel J; Lashley, Tammaryn; Stevens, Beth; Chang, Sunghoe; Hong, Soyon.
Afiliação
  • Rueda-Carrasco J; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
  • Sokolova D; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
  • Lee SE; Neuroscience BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • Childs T; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
  • Jurcáková N; Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
  • Crowley G; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
  • De Schepper S; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
  • Ge JZ; Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
  • Lachica JI; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
  • Toomey CE; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
  • Freeman OJ; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
  • Hardy J; The Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.
  • Barnes SJ; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
  • Lashley T; The Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.
  • Stevens B; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
  • Chang S; Neuroscience BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • Hong S; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
EMBO J ; 42(19): e113246, 2023 Oct 04.
Article em En | MEDLINE | ID: mdl-37575021
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 Aß 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 Aß 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 Aß-relevant context and suggest a potential beneficial role for microglia in the earliest stages of AD.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer Limite: Animals / Humans Idioma: En Revista: EMBO J Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença de Alzheimer Limite: Animals / Humans Idioma: En Revista: EMBO J Ano de publicação: 2023 Tipo de documento: Article