Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse.
Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse.
复制标题
神经元 seipin 敲除通过减少小鼠海马中的 PPARgamma 促进 Abeta 诱导的神经炎症和神经毒性。
DOI：
10.1186/s12974-016-0598-3
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发表时间：
2016-06-10
影响因子：
9.3
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Qian Y;Yin J;Hong J;Li G;Zhang B;Liu G;Wan Q;Chen L
由 seipin 基因功能丧失引起的先天性全身性脂肪营养不良 2 (CGL2) 的一个特征表型是智力低下。 Seipin 在海马锥体细胞和星形胶质细胞中高表达。小鼠（seipin-KO 小鼠）神经元敲除 seipin 会降低海马过氧化物酶体增殖物激活受体 γ (PPARγ) 水平，而不会损失锥体细胞。 PPARγ 的下调在阿尔茨海默病 (AD) 的神经炎症中受到越来越多的关注。因此，本研究重点探讨 seipin 耗竭对 β-淀粉样蛋白 (Aβ) 诱导的神经炎症和 Aβ 神经毒性的影响。成年雄性 seipin-KO 小鼠接受单次脑室内 (i.c.v.) 注射 Aβ25–35（1.2 nmol/小鼠）或 Aβ1–42（0.1 nmol/小鼠），这对野生型 (WT) 小鼠来说通常是非神经毒性剂量。通过 Morris 水迷宫和 Y 迷宫测试评估空间认知行为，并检查海马 CA1 锥体细胞和炎症反应。在 seipin-KO 小鼠中注射 Aβ25–35/1–42 导致大约 30–35% 的锥体细胞死亡，并产生 Hoechst 阳性细胞，并导致空间记忆受损。与WT小鼠相比，seipin-KO小鼠的星形胶质细胞和小胶质细胞数量无显着差异，而IL-6和TNF-α水平略有升高。同样，seipin-KO 小鼠而非 WT 小鼠中注射 Aβ25-35/1-42 可以刺激星形胶质细胞或小胶质细胞的活化，并进一步升高 IL-6 和 TNF-α 的水平。用 PPARγ 激动剂罗格列酮 (rosi) 治疗 seipin-KO 小鼠可以预防 Aβ25-35/1-42 诱导的神经炎症和神经毒性，而这种作用可被 PPARγ 拮抗剂 GW9962 阻断。在seipin-KO小鼠中，与WT小鼠相比，Tyr216处的糖原合酶激酶-3β（GSK3β）磷酸化水平升高，而Ser9处的磷酸化水平降低，WT小鼠通过rosi治疗得到纠正，但不受Aβ25-35注射的影响。星形胶质细胞中的 Seipin 缺陷通过减少 PPARγ 增加 GSK3β 活性以及 IL-6 和 TNF-α 水平，从而促进 Aβ25–35/1–42 诱导的神经炎症，导致神经元细胞死亡和认知缺陷。本文的在线版本 (doi:10.1186/s12974-016-0598-3) 包含补充材料，可供授权用户使用。
A characteristic phenotype of congenital generalized lipodystrophy 2 (CGL2) that is caused by loss-of-function of seipin gene is mental retardation. Seipin is highly expressed in hippocampal pyramidal cells and astrocytes. Neuronal knockout of seipin in mice (seipin-KO mice) reduces the hippocampal peroxisome proliferator-activated receptor gamma (PPARγ) level without the loss of pyramidal cells. The down-regulation of PPARγ has gained increasing attention in neuroinflammation of Alzheimer’s disease (AD). Thus, the present study focused on exploring the influence of seipin depletion on β-amyloid (Aβ)-induced neuroinflammation and Aβ neurotoxicity. Adult male seipin-KO mice were treated with a single intracerebroventricular (i.c.v.) injection of Aβ25–35 (1.2 nmol/mouse) or Aβ1–42 (0.1 nmol/mouse), generally a non-neurotoxic dose in wild-type (WT) mice. Spatial cognitive behaviors were assessed by Morris water maze and Y-maze tests, and hippocampal CA1 pyramidal cells and inflammatory responses were examined. The Aβ25–35/1–42 injection in the seipin-KO mice caused approximately 30–35 % death of pyramidal cells and production of Hoechst-positive cells with the impairment of spatial memory. In comparison with the WT mice, the number of astrocytes and microglia in the seipin-KO mice had no significant difference, whereas the levels of IL-6 and TNF-α were slightly increased. Similarly, the Aβ25–35/1–42 injection in the seipin-KO mice rather than the WT mice could stimulate the activation of astrocytes or microglia and further elevated the levels of IL-6 and TNF-α. Treatment of the seipin-KO mice with the PPARγ agonist rosiglitazone (rosi) could prevent Aβ25–35/1–42-induced neuroinflammation and neurotoxicity, which was blocked by the PPARγ antagonist GW9962. In the seipin-KO mice, the level of glycogen synthase kinase-3β (GSK3β) phosphorylation at Tyr216 was elevated, while at Ser9, it was reduced compared to the WT mice, which were corrected by the rosi treatment but were unaffected by the Aβ25–35 injection. Seipin deficiency in astrocytes increases GSK3β activity and levels of IL-6 and TNF-α through reducing PPARγ, which can facilitate Aβ25–35/1–42-induced neuroinflammation to cause the death of neuronal cells and cognitive deficits. The online version of this article (doi:10.1186/s12974-016-0598-3) contains supplementary material, which is available to authorized users.