Identifying the role of RIPK1 in Alzheimer's disease

阿尔茨海默病(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。阐明阿尔茨海默病神经元丢失的机制将对阿尔茨海默病的发展具有重要意义 新的治疗方法。在本申请中，我们将重点放在坏死性下垂，一种程序性的坏死形式， 由受体相互作用蛋白激酶(RIPK)1和3触发，并由混合血统激酶执行 结构域样(MLKL)蛋白。当被多种炎症应激源激活时，RIPK1与RIPK3结合形成 一种被称为坏死体的多蛋白复合体，足以激活坏死性下垂。僵尸形态 在自噬体膜上，突出了坏死性下垂和自噬之间的密切相互作用。我们 提供令人信服的证据表明，坏死性下垂在AD时被激活，在那里它可能有助于 神经退行性变。我们和其他人一直在报道，在AD的大脑中，RIPK1在 小胶质细胞和神经元。我们还生成了一个因果基因调控网络来模拟AD中RIPK1的相互作用 并发现RIPK1活性可能解释了AD转录变化的很大一部分原因。我们进一步展示了 这种降低RIPK1活性的药理作用可以减少5xFAD小鼠的神经元丢失。在此应用程序中，我们 将测试RIPK1通过激活RIPK1导致AD神经退行性变这一重要假设 坏死性下垂。具体目标1将确定小胶质细胞和神经元RIPK1在AD中的作用。特定目标2将 确定RIPK1介导的AD坏死性下垂的激活机制。特定目标3将确定新的 阻断RIPK1介导的神经变性的策略。影响：神经元死亡的机制仍然是 未知。我们认为RIPK1介导的坏死性下垂是AD和AD神经退行性变的重要机制。 建议进行实验，剖析这种蛋白激酶在这种潜伏性疾病中的作用。我们的结果将开启新的 为AD的研究和干预提供机会，并将确定要阻止的新的高翻译化合物 坏死性下垂激活。

Severe neuronal loss characterizes Alzheimer's disease (AD); however, the mechanisms by which neurons die remain elusive. Elucidating the mechanisms underlying neuronal loss in AD will be invaluable to the development of new therapeutic approaches. In this application, we focus on necroptosis, a programmed form of necrosis, triggered by receptor-interactive protein kinases (RIPK) 1 and 3 and executed by the mixed lineage kinase domain-like (MLKL) protein. Upon activation by multiple inflammatory stressors, RIPK1 binds to RIPK3 to form a multiprotein complex known as necrosome, which is sufficient for necroptosis activation. The necrosome forms on the membrane of autophagosomes highlighting a close interaction between necroptosis and autophagy. We provide compelling evidence showing that necroptosis is activated in AD where it may contribute to neurodegeneration. Consistently, we and others have reported that in AD brains RIPK1 is upregulated in microglia and neurons. We also generated a causal gene regulatory network to model RIPK1 interactions in AD and found that RIPK1 activity may explain a significant portion of transcriptomic changes in AD. We further show that pharmacologically decreasing RIPK1 activity reduces neuronal loss in 5xFAD mice. In this application, we will test the overarching hypothesis that RIPK1 contributes to neurodegeneration in AD by activating necroptosis. Specific Aim 1 will identify the role of microglial and neuronal RIPK1 in AD. Specific Aim 2 will determine the mechanisms of RIPK1-mediated necroptosis activation in AD. Specific Aim 3 will identify new strategies to block RIPK1-mediated neurodegeneration. Impact: The mechanisms by which neurons die are still unknown. We propose that RIPK1-mediated necroptosis is a crucial mechanism of neurodegeneration in AD and propose experiments to dissect the role of this protein kinase in this insidious disorder. Our results will open new opportunities for research and interventions for AD and will identify new highly translational compounds to block necroptosis activation.