比利時(shí)魯汶腦與疾病研究中心Bart De Strooper團(tuán)隊(duì)近期取得重要工作進(jìn)展，他們研究發(fā)現(xiàn)，MEG3能夠激活阿爾茲海默病模型中異種移植神經(jīng)元的壞死性死亡。相關(guān)研究成果2023年9月15日在線發(fā)表于《科學(xué)》雜志上。
據(jù)介紹，神經(jīng)元細(xì)胞丟失是阿爾茨海默（AD）的一個(gè)決定性特征，但其潛在機(jī)制仍不清楚。
研究人員將將人類或小鼠神經(jīng)元異種移植到AD小鼠模型的大腦中。只有人類神經(jīng)元表現(xiàn)出纏結(jié)、Gallyas銀染色、顆?？张萆窠?jīng)退化（GVD）、tau血生物標(biāo)志物磷酸化和大量神經(jīng)元細(xì)胞損失。長鏈非編碼RNA MEG3在人類神經(jīng)元中強(qiáng)烈上調(diào)。這種神經(jīng)元特異性長非編碼RNA在AD患者中也發(fā)生上調(diào)。單獨(dú)的MEG3表達(dá)足以在體外誘導(dǎo)人類神經(jīng)元壞死性凋亡。通過藥理或基因操作受體相互作用蛋白激酶1 (RIPK1)、RIPK3或混合譜系激酶結(jié)構(gòu)域樣蛋白（MLKL）來下調(diào)MEG3和抑制壞死垂亡，可挽救異種移植人類神經(jīng)元中的神經(jīng)元細(xì)胞損失。
總之，該模型提出了AD的潛在治療方法，并揭示了人類特有的AD易感性機(jī)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
期刊信息
Science：《科學(xué)》，創(chuàng)刊于1880年。隸屬于美國科學(xué)促進(jìn)會(huì)，最新IF：63.714
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