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MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease

Balusu, Sriram; Horré, Katrien; Thrupp, Nicola; Craessaerts, Katleen; Snellinx, An; Serneels, Lutgarde; T'Syen, Dries; ... De Strooper, Bart; + view all (2023) MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease. Science , 381 (6663) pp. 1176-1182. 10.1126/science.abp9556. Green open access

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Abstract

Neuronal cell loss is a defining feature of Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human neurons. This neuron-specific long noncoding RNA is also up-regulated in AD patients. MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of MEG3 and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD.

Type: Article
Title: MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/science.abp9556
Publisher version: https://doi.org/10.1126/science.abp9556
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
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
URI: https://discovery.ucl.ac.uk/id/eprint/10178131
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