The blockage of the Nogo/NgR signal pathway in microglia alleviates the formation of Aβ plaques and tau phosphorylation in APP/PS1 transgenic mice
The blockage of the Nogo/NgR signal pathway in microglia alleviates the formation of Aβ plaques and tau phosphorylation in APP/PS1 transgenic mice
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阻断小胶质细胞中的 Nogo/NgR 信号通路可减轻 APP/PS1 转基因小鼠中 Aβ 斑块的形成和 tau 磷酸化
DOI：
10.1186/s12974-016-0522-x
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发表时间：
2016-03-03
影响因子：
9.3
通讯作者：
Liao, Hong
中科院分区：
文献类型：
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作者：
Fang, Yinquan;Yao, Lemeng;Liao, Hong
背景资料：阿尔茨海默病（AD）的特征在于细胞外β-淀粉样蛋白（A β）斑块、神经纤维缠结（NFT）和小胶质细胞主导的神经炎症。Nogo/NgR信号通路参与了AD的病理过程，但具体机制有待进一步研究。我们前期的研究证实Nogo通过激活小胶质细胞表面NgR，促进促炎细胞因子的表达，抑制细胞的粘附和迁移行为。方法：侧脑室注射Nogo/NgR通路竞争性拮抗剂NEP 1 -40，通过微量渗透泵给淀粉样前体蛋白（APP）/PS1转基因小鼠2个月，观察斑块负荷、tau蛋白磷酸化和炎症反应。结果：Nogo/NgR信号通路的抑制可改善APP/PS1小鼠的病理特征，包括淀粉样斑块和tau蛋白磷酸化水平。此外，用来自Nogo刺激的BV-2小胶质细胞的条件培养基处理后，培养神经元中A β产生和tau磷酸化增加。条件培养基还增加了APP的表达、其淀粉样蛋白的加工以及神经元中GSK 3 β的活性。结论：Nogo/NgR通路介导的小胶质细胞炎症反应可能通过影响淀粉样蛋白的生成和tau蛋白的磷酸化直接参与了AD的病理过程。这些结果有助于更好地了解AD的发病机制，并可能为延缓AD的进展提供新的治疗选择。
Background: Alzheimer's disease (AD) is characterized by extracellular beta-amyloid (A beta) plaques, neurofibrillary tangles (NFTs), and microglia-dominated neuroinflammation. The Nogo/NgR signal pathway is involved in AD pathological features, but the detailed mechanism needs further investigation. Our previous studies have confirmed that the activation of NgR on microglia by Nogo promotes the expression of proinflammatory cytokines and inhibits cell adhesion and migration behaviors. In the present study, we investigated the effects of Nogo/NgR signaling pathway on the pathological features of AD and possible mechanisms.Methods: After NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in amyloid precursor protein (APP)/PS1 transgenic mice, plaque load, tau phosphorylation, and inflammatory responses were determined. After primary mouse neurons were exposed to the conditioned medium from BV-2 microglia stimulated by Nogo, the production of A beta and phosphorylation of tau was quantified by ELISA and western blot.Results: Inhibition of the Nogo/NgR signaling pathway ameliorated pathological features including amyloid plaques and phosphorylated levels of tau in APP/PS1 mice. In addition, after treatment with the conditioned medium from BV-2 microglia stimulated by Nogo, A beta production and tau phosphorylation in cultured neurons were increased. The conditioned medium also increased the expression of APP, its amyloidogenic processing, and the activity of GSK3 beta in neurons. The conditioned medium was also proinflammatory medium, and the blockage of the Nogo/NgR pathway improved the neuroinflammatory environment in APP/PS1 mice.Conclusions: Taken together, the neuroinflammation mediated by Nogo/NgR pathway in microglia could directly take part in the pathological process of AD by influencing the amyloidogenesis and tau phosphorylation. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying the progression of AD.