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

التفاصيل البيبلوغرافية
العنوان: Microglia-synapse engulfment via PtdSer-TREM2 ameliorates neuronal hyperactivity in Alzheimer's disease models.
المؤلفون: 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.; Neuroscience BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Lee SE; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.; Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea., Childs T; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK., Jurčáková N; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.; Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK., 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; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK., Lachica JI; The Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK., Toomey CE; The Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK., Freeman OJ; Neuroscience BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Hardy J; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK., Barnes SJ; UK Dementia Research Institute, Department of Brain Sciences, Imperial College London, London, UK., Lashley T; The Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.; Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK., Stevens B; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA., Chang S; Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea., Hong S; UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
المصدر: The EMBO journal [EMBO J] 2023 Oct 04; Vol. 42 (19), pp. e113246. Date of Electronic Publication: 2023 Aug 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE
أسماء مطبوعة: Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-
مواضيع طبية MeSH: Alzheimer Disease*/genetics, Humans ; Mice ; Animals ; Microglia ; Synapses ; Disease Models, Animal ; Amyloid beta-Peptides/genetics ; Membrane Glycoproteins/genetics ; Receptors, Immunologic/genetics
مستخلص: 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.
(© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)
التعليقات: Erratum in: EMBO J. 2024 Jul 31. doi: 10.1038/s44318-024-00159-5. (PMID: 39085649)
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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust
فهرسة مساهمة: Keywords: Abeta oligomers; Alzheimer's disease; microglia; pruning; synapses
المشرفين على المادة: 0 (Amyloid beta-Peptides)
0 (TREM2 protein, human)
0 (Membrane Glycoproteins)
0 (Receptors, Immunologic)
تواريخ الأحداث: Date Created: 20230814 Date Completed: 20240129 Latest Revision: 20240731
رمز التحديث: 20240801
مُعرف محوري في PubMed: PMC10548173
DOI: 10.15252/embj.2022113246
PMID: 37575021
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2075
DOI:10.15252/embj.2022113246