Yao Jing, Li Yuan, Liu Xi, Liang Wenping, Li Yu, Wu Liyong, Wang Zhe, Song Weihong
The National Clinical Research Center for Geriatric Disease, Xuanwu Hospital, Capital Medical University, Beijing, China.
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
Neural Regen Res. 2025 Jul 1;20(7):2068-2083. doi: 10.4103/NRR.NRR-D-23-01799. Epub 2024 May 13.
JOURNAL/nrgr/04.03/01300535-202507000-00028/figure1/v/2024-09-09T124005Z/r/image-tiff Alzheimer's disease is characterized by deposition of amyloid-β, which forms extracellular neuritic plaques, and accumulation of hyperphosphorylated tau, which aggregates to form intraneuronal neurofibrillary tangles, in the brain. The NLRP3 inflammasome may play a role in the transition from amyloid-β deposition to tau phosphorylation and aggregation. Because NLRP3 is primarily found in brain microglia, and tau is predominantly located in neurons, it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines. Here, we found that neurons also express NLRP3 in vitro and in vivo, and that neuronal NLRP3 regulates tau phosphorylation. Using biochemical methods, we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons. In primary neurons and the neuroblastoma cell line Neuro2A, FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-β is present. In the brains of aged wild-type mice and a mouse model of Alzheimer's disease, FUBP3 expression was markedly increased in cortical neurons. Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses. We also found that FUBP3 trimmed the 5' end of DNA fragments that it bound, implying that FUBP3 functions in stress-induced responses. These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to-phospho-tau transition than microglial NLRP3, and that amyloid-β fundamentally alters the regulatory mechanism of NLRP3 expression in neurons. Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice, FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.
《阿尔茨海默病以β-淀粉样蛋白沉积为特征，β-淀粉样蛋白在大脑中形成细胞外神经炎斑块，以及过度磷酸化的tau蛋白积累，tau蛋白聚集形成神经元内神经原纤维缠结。NLRP3炎性小体可能在从β-淀粉样蛋白沉积到tau蛋白磷酸化和聚集的转变中起作用。由于NLRP3主要存在于脑小胶质细胞中，而tau蛋白主要位于神经元中，有人提出小胶质细胞表达的NLRP3通过上调促炎细胞因子的表达间接触发tau蛋白磷酸化。在这里，我们发现神经元在体外和体内也表达NLRP3，并且神经元NLRP3调节tau蛋白磷酸化。使用生化方法，我们绘制了最小的NLRP3启动子图谱，并确定FUBP3是调节神经元中NLRP3表达的转录因子。在原代神经元和神经母细胞瘤细胞系Neuro2A中，仅当存在β-淀粉样蛋白时，FUBP3才是内源性NLRP3表达和tau蛋白磷酸化所必需的。在老年野生型小鼠和阿尔茨海默病小鼠模型的大脑中，皮质神经元中FUBP3的表达明显增加。转录组分析表明FUBP3在神经元介导的免疫反应中起作用。我们还发现FUBP3修剪了它所结合的DNA片段的5'末端，这意味着FUBP3在应激诱导的反应中起作用。这些发现表明，与小胶质细胞NLRP3相比，神经元NLRP3可能更直接地参与β-淀粉样蛋白向磷酸化tau蛋白的转变，并且β-淀粉样蛋白从根本上改变了神经元中NLRP3表达的调节机制。鉴于FUBP3在年轻野生型小鼠中仅低水平表达，而在老年小鼠和阿尔茨海默病小鼠的大脑中强烈上调，FUBP3可能是预防阿尔茨海默病进展的安全治疗靶点。 》 （注：原文中“JOURNAL/nrgr/04.03/01300535-202507000-00028/figure1/v/2024-09-09T124005Z/r/image-tiff”这段内容看起来像是文献中的一个路径之类的标识，在翻译时保留原样未做处理，因为其本身不属于有实际语义需要翻译的部分。）
