比利时鲁汶脑与疾病研究中心Bart De Strooper团队近期取得重要工作进展，他们研究发现，MEG3能够激活阿尔兹海默病模型中异种移植神经元的坏死性死亡。相关研究成果2023年9月15日在线发表于《科学》杂志上。

据介绍，神经元细胞丢失是阿尔茨海默（AD）的一个决定性特征，但其潜在机制仍不清楚。

研究人员将将人类或小鼠神经元异种移植到AD小鼠模型的大脑中。只有人类神经元表现出缠结、Gallyas银染色、颗粒空泡神经退化（GVD）、tau血生物标志物磷酸化和大量神经元细胞损失。长链非编码RNA MEG3在人类神经元中强烈上调。这种神经元特异性长非编码RNA在AD患者中也发生上调。单独的MEG3表达足以在体外诱导人类神经元坏死性凋亡。通过药理或基因操作受体相互作用蛋白激酶1 (RIPK1)、RIPK3或混合谱系激酶结构域样蛋白（MLKL）来下调MEG3和抑制坏死垂亡，可挽救异种移植人类神经元中的神经元细胞损失。

总之，该模型提出了AD的潜在治疗方法，并揭示了人类特有的AD易感性机制。

附：英文全文

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

Author: Sriram Balusu, Katrien Horré, Nicola Thrupp, Katleen Craessaerts, An Snellinx, Lutgarde Serneels, Dries T’Syen, Iordana Chrysidou, Amaia M. Arranz, Annerieke Sierksma, Joel Simrén, Thomas K. Karikari, Henrik Zetterberg, Wei-Ting Chen, Dietmar Rudolf Thal, Evgenia Salta, Mark Fiers, Bart De Strooper

Issue&Volume: 2023-09-15

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.

DOI: abp9556

Source: https://www.science.org/doi/10.1126/science.abp9556