Science (New York, N.Y.) · 2023
MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
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Balusu Sriram, Horré Katrien, Thrupp Nicola, Craessaerts Katleen, Snellinx An, Serneels Lutgarde, T'Syen Dries, Chrysidou Iordana, Arranz Amaia M, Sierksma Annerieke, Simrén Joel, Karikari Thomas K, Zetterberg Henrik, Chen Wei-Ting, Thal Dietmar Rudolf, Salta Evgenia, Fiers Mark, De Strooper Bart
Аннотация
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.