Alzheimer’s disease is an irreversible neurodegenerative disease, which accounts for most dementia cases. Neuroinflammation is increasingly recognised for its roles in Alzheimer’s disease pathogenesis which, in part, links amyloid-beta to neuronal death. Neuroinflammatory signalling can be exhibited by neurons themselves, potentially leading to widespread neuronal cell death, although neuroinflammation is commonly associated with glial cells. The presence of the inflammasomes such as nucleotide-binding leucine-rich repeat receptors protein 1 in neurons accelerates amyloid-beta -induced neuroinflammation and has been shown to trigger neuronal pyroptosis in murine Alzheimer’s disease models. However, the pathways involved in amyloid-beta activation of inflammasomes have yet to be elucidated. In this study, a gene trap mutagenesis approach was utilised to resolve the genes functionally involved in inflammasome signalling within neurons, and the mechanism behind amyloid-beta-induced neuronal death. The results indicate that amyloid-beta significantly accelerated neuroinflammatory cell death in the presence of a primed inflammasome (the NLR family pyrin domain-containing 1). The mutagenesis screen discovered the atypical mitochondrial Ras homolog family member T1 as a significant contributor to amyloid-beta-induced inflammasome -mediated neuronal death. The mutagenesis screen also identified two genes involved in transforming growth factor beta signalling, namely Transforming Growth Factor Beta Receptor 1 and SNW domain containing 1. Additionally, a gene associated with cytoskeletal reorganisation, SLIT-ROBO Rho GTPase Activating Protein 3 was found to be neuroprotective. In conclusion, these genes could play important roles in inflammasome signalling in neurons, which makes them promising therapeutic targets for future drug development against neuroinflammation in Alzheimer’s disease.

阿尔茨海默病是一种不可逆的神经退行性疾病，是大多数痴呆病例的原因。神经炎症因其在阿尔茨海默病发病机制中的作用而得到越来越多的认可，这部分地将淀粉样蛋白-β 与神经元死亡联系起来。神经炎症信号可以由神经元本身表现出来，可能导致广泛的神经元细胞死亡，尽管神经炎症通常与神经胶质细胞有关。神经元中诸如核苷酸结合的富含亮氨酸的重复受体蛋白 1 等炎症小体的存在会加速淀粉样蛋白 β 诱导的神经炎症，并已显示在小鼠阿尔茨海默病模型中引发神经元焦亡。然而，炎症小体的淀粉样蛋白-β 激活所涉及的途径尚未阐明。在这项研究中，使用基因陷阱诱变方法来解析功能上参与神经元内炎症小体信号传导的基因，以及淀粉样蛋白 β 诱导的神经元死亡背后的机制。结果表明，淀粉样蛋白-β 在引发炎症小体（包含 NLR 家族 pyrin 结构域 1）的情况下显着加速了神经炎症细胞死亡。诱变筛选发现非典型线粒体 Ras 同源家族成员 T1 是淀粉样蛋白 β 诱导的炎症小体介导的神经元死亡的重要因素。诱变筛选还确定了两个参与转化生长因子 β 信号传导的基因，即转化生长因子 Beta 受体 1 和含有 1 的 SNW 结构域。此外，一个与细胞骨架重组相关的基因，SLIT-ROBO Rho GTPase Activating Protein 3 被发现具有神经保护作用。总之，这些基因可能在神经元的炎症小体信号传导中发挥重要作用，这使它们成为未来针对阿尔茨海默病神经炎症的药物开发的有希望的治疗靶点。