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

• 成果类型: Article
• 署名作者: Balusu, Sriram; Horre, Katrien; Thrupp, Nicola; Craessaerts, Katleen; Snellinx, An; Serneels, Lutgarde; T'Syen, Dries; Chrysidou, Iordana; Arranz, Amaia M.; Sierksma, Annerieke; Simren, Joel; Karikari, Thomas K.; Zetterberg, Henrik; Chen, Wei-Ting; Thal, Dietmar Rudolf; Salta, Evgenia; Fiers, Mark; De Strooper, Bart
• 署名单位: Flanders Institute for Biotechnology (VIB); KU Leuven; Basque Foundation for Science; Sahlgrenska University Hospital; University of Gothenburg; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of London; University College London; University of London; University College London; KU Leuven; KU Leuven; University Hospital Leuven; Royal Netherlands Academy of Arts & Sciences; Netherlands Institute for Neuroscience (NIN-KNAW)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10245
• DOI: 10.1126/science.abp9556
• 发表日期: 2023-09-15
• 页码: 1176-+
• 关键词: noncoding rna; beta plaques; a-beta; expression; pathology; tau

摘要

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.