Alzheimer's disease (AD) is characterized by severe neuronal loss; however, the mechanisms by which neurons die remain elusive. Necroptosis, a programmed form of necrosis, is executed by the mixed lineage kinase domain-like (MLKL) protein, which is triggered by receptor-interactive protein kinases (RIPK) 1 and 3. We found that necroptosis was activated in postmortem human AD brains, positively correlated with Braak stage, and inversely correlated with brain weight and cognitive scores. In addition, we found that the set of genes regulated by RIPK1 overlapped significantly with multiple independent AD transcriptomic signatures, indicating that RIPK1 activity could explain a substantial portion of transcriptomic changes in AD. Furthermore, we observed that lowering necroptosis activation reduced cell loss in a mouse model of AD. We anticipate that our findings will spur a new area of research in the AD field focused on developing new therapeutic strategies aimed at blocking its activation.

中文翻译：

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阿尔茨海默氏病中的坏死病激活。

阿尔茨海默氏病（AD）的特征是严重的神经元丢失；然而，神经元死亡的机制仍然难以捉摸。坏死病是一种坏死的程序化形式，由混合谱系激酶结构域样（MLKL）蛋白执行，它由受体相互作用蛋白激酶（RIPK）1和3触发。我们发现死后人类AD脑中有坏死病激活。 ，与Braak阶段呈正相关，与脑重量和认知得分呈反相关。此外，我们发现受RIPK1调控的基因集与多个独立的AD转录组签名显着重叠，表明RIPK1活性可以解释AD转录组变化的很大一部分。此外，我们观察到降低坏死病激活减少了AD小鼠模型中的细胞损失。