Necroptosis activation in Alzheimer's disease
Necroptosis activation in Alzheimer's disease
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DOI：
10.1038/nn.4608
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发表时间：
2017-09-01
影响因子：
25
通讯作者：
Oddo, Salvatore
中科院分区：
文献类型：
--
作者：
Caccamo, Antonella;Branca, Caterina;Oddo, Salvatore
阿尔茨海默病（AD）的特征在于严重的神经元损失;然而，神经元死亡的机制仍然难以捉摸。坏死性凋亡是一种程序性坏死，由混合谱系激酶结构域样（MLKL）蛋白执行，其由受体相互作用蛋白激酶（RIPK）1和3触发。我们发现，坏死性凋亡被激活，在死后的人类AD大脑，正相关的Braak阶段，与脑重量和认知评分呈负相关。此外，我们发现RIPK 1调控的基因组与多个独立的AD转录组特征显著重叠，表明RIPK 1活性可以解释AD中相当大一部分的转录组变化。此外，我们观察到降低坏死性凋亡激活减少了AD小鼠模型中的细胞损失。我们预计，我们的研究结果将刺激AD领域的一个新的研究领域，重点是开发旨在阻断其激活的新治疗策略。
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.