VGF (TLQP-62)-induced neurogenesis targets early phase neural progenitor cells in the adult hippocampus and requires glutamate and BDNF signaling.
VGF (TLQP-62)-induced neurogenesis targets early phase neural progenitor cells in the adult hippocampus and requires glutamate and BDNF signaling.
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DOI：
10.1016/j.scr.2014.03.005
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发表时间：
2014-05
影响因子：
1.2
通讯作者：
Alder J
中科院分区：
文献类型：
--
作者：
Thakker-Varia S;Behnke J;Doobin D;Dalal V;Thakkar K;Khadim F;Wilson E;Palmieri A;Antila H;Rantamaki T;Alder J
TBI 后神经营养蛋白水平升高，但再生程度极低。据推测，前神经营养蛋白/p75NTR 通路比成熟神经营养蛋白/Trk 通路更容易被诱导，并且干扰 p75 信号传导可改善 TBI 后的恢复。对野生型和 p75 突变小鼠进行横向流体冲击 (LFP) 损伤。此外，还测试了TrkB激动剂7,8二羟基黄酮或p75拮抗剂TAT-Pep5。蛋白质印迹和免疫组织化学揭示了生化和细胞变化。莫里斯水迷宫和旋转测试证明了认知和前庭运动功能。 LFP 后 1 天，p75 上调，TrkB 下调。 p75突变小鼠以及用p75拮抗剂或TrkB激动剂治疗的小鼠表现出神经元死亡和变性减少以及星形细胞增多。经历凋亡的细胞似乎是神经元而不是神经胶质细胞。 p75 突变小鼠和 p75 拮抗剂治疗小鼠的运动功能和空间学习能力得到改善。 TBI 的许多病理和行为后果可能是由于前神经营养蛋白/p75 毒性途径的激活超越了成熟神经营养蛋白/Trk 途径的保护机制。靶向 p75 可能是抵消 TBI 破坏性影响的新策略。
Neurotrophin levels are elevated after TBI yet there is minimal regeneration. It was hypothesized that the pro-neurotrophin/p75NTR pathway is induced more than the mature neurotrophin/Trk pathway and that interfering with p75 signaling improves recovery following TBI. Lateral Fluid Percussion (LFP) injury was performed on wildtype and p75 mutant mice. In addition, TrkB agonist 7,8 Dihydroxyflavone or p75 antagonist TAT-Pep5 were tested. Western blot and immunohistochemistry revealed biochemical and cellular changes. Morris Water Maze and Rotarod tests demonstrated cognitive and vestibulomotor function. p75 was upregulated and TrkB is downregulated 1 day post LFP. p75 mutant mice as well as mice treated with the p75 antagonist or the TrkB agonist exhibited reduced neuronal death and degeneration and less astrocytosis. The cells undergoing apoptosis appear to be neurons rather than glia. There was improved motor function and spatial learning in p75 mutant mice and mice treated with the p75 antagonist. Many of the pathological and behavioural consequences of TBI might be due to activation of the pro-neurotrophin/p75 toxic pathway overriding the protective mechanisms of the mature neurotrophin/Trk pathway. Targeting p75 can be a novel strategy to counteract the damaging effects of TBI.