biostudies-literatureBalusu SEuropean Research CouncilAlzheimer's Society1176-1182https://www.ebi.ac.uk/biostudies/studies/S-EPMC7615236biostudies-literatureUnknown381(6663)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 <i>MEG3</i> was strongly up-regulated in human neurons<i>.</i> This neuron-specific long noncoding RNA is also up-regulated in AD patients. <i>MEG3</i> expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of <i>MEG3</i> 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.Science (New York, N.Y.)MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease.PMC7615236MR/Y014847/1430834682720931681712438Balusu SSalta EThal DRDe Strooper BSimren JZetterberg HHorre KChen WTFiers MT'Syen DChrysidou IArranz AMCraessaerts KSierksma AThrupp NKarikari TKSnellinx ASerneels LfalseMEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease.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 <i>MEG3</i> was strongly up-regulated in human neurons<i>.</i> This neuron-specific long noncoding RNA is also up-regulated in AD patients. <i>MEG3</i> expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of <i>MEG3</i> 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.2023-01-01T00:00:00Z2023 Sep2024-11-20T20:54:29.073Z2024-11-20T20:54:29.073ZS-EPMC76152363770827210.1126/science.abp9556