小鼠慢性应激模型海马中tau蛋白磷酸化及其对线粒体轴浆运输的影响
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摘要
Tau蛋白是一种微管相关蛋白,其磷酸化受到严格调控,在神经元中和轴浆运输密切相关。据研究报道,急性应激中,啮齿类动物海马中tau蛋白的磷酸化和下丘脑-垂体-肾上腺(Hypothalamo-Pituitary-Adrenal,HPA)轴的过度激活密切相关。而在抑郁病人中,HPA轴的过度激活是基本的特征之一。因此,在抑郁症中,tau蛋白的磷酸化情况以及和轴浆运输的关系需要进一步研究。我们的假设是:在抑郁模型中,HPA轴的过度激活会引起tau蛋白的过度磷酸化并进一步影响到轴浆运输。
为验证该假设,我们首先建立了母子剥夺抑郁模型,对其进行了行为学测试,并检测了HPA轴活性。然后检测了海马中tau蛋白的磷酸化水平。为了研究轴浆运输的变化,我们选择了检测海马突触体中线粒体水平的变化。结合CRH(Corticotropin-Releasing Hormone,CRH)受体1(CRH Receptor1,CRHR1)和糖皮质激素受体(Glucocorticoid Receptor,GR)的拮抗剂,研究了CRH直接的中枢作用机制和HPA轴的反馈机制在tau蛋白磷酸化和线粒体运输中的作用,。为了进一步检测tau蛋白磷酸化和线粒体运输的关系,我们用实时成像技术,观察当原代神经元中tau蛋白磷酸化水平发生变化时线粒体运输的动态变化。结果发现:
1.母子剥夺抑郁模型具有典型的抑郁样行为和过度激活的HPA轴。
在旷场、糖水偏好和明暗箱行为学测试中,抑郁模型具有典型的抑郁样行为。和对照组相比,抑郁模型具有显著升高的血浆cortitosterone和下丘脑CRH mRNA水平。
2.抑郁模型海马中tau蛋白的磷酸化水平显著升高。
和对照组相比,抑郁鼠的海马中tau蛋白的总表达水平没有显著变化,但在在AT-8磷酸化位点显著升高,在tau-1非磷酸化位点显著降低。
3.抑郁模型海马突触体中的线粒体水平显著升高。
和对照组相比,抑郁模型海马突触体中的线粒体水平显著升高。
4. CRHR1而不是GR介导了tau蛋白的磷酸化水平升高和突触体中线粒体水平的升高。
CRHR1的拮抗剂CP154526能显著降低tau蛋白的磷酸化,并能恢复突触体中线粒体的水平,而GR的拮抗剂RU486却没有这些作用。
5.在原代神经元中,当tau蛋白磷酸化水平降低时,线粒体的轴浆运输水平下调。我们用锂盐抑制Gsk3beta的活性从而降低原代神经元中tau蛋白的磷酸化水
平,我们观察到线粒体的轴浆运输水平显著下降。
上述结果表明,在抑郁模型中CRHR1介导了tau蛋白的过度磷酸化,同时伴随着突触体中线粒体水平的升高。这向我们揭示,在抑郁模型中,CRH的中枢作用参与了线粒体运输的调控,这可能为研究抑郁发病机制提出了一条新思路。
Corticotropin-releasing hormone (CRH) is considered as the driving force for hypothalamo-pituitary-adrenal (HPA) axis and play an important role in mood regulation. HPA axis is reported to be closely related to acute stress induced tau phosphorylation in rodent hippocampus. However, the relationship between the hyperactive HPA axis and tau phosphorylation in hippocampus and hence the functional implications in depression are not fully understood. In the present study, we aimed to examine the tau phosphorylation and the effect on axon transport of mitochondria in hippocampus of a depression model. A mice depression model was made by neonatal isolation before weaning, followed by chronic mild stress by social isolation after weaning. Behavior tests showed that the model had a typical depression-like behavior accompanied by increased plasma corticosterone level and hypothalamic CRH mRNA expression. The phosphorylated tau increased significantly, accompanied by increased synaptosome mitochondria level in hippocampus of the depression model. CRH receptor1 antagonist (CP154 526) treatment, not glucocorticoid receptor antagonist (RU486) treatment, decreased tau phosphorylation level, and restored synaptosome mitochondria level in model hippocampus. Moreover, when hyperphosphorylated tau was inhibited by lithium, the mitochondria transport monitored by live imaging was decreased in cultured primary hippocampus neuron. We showed here for the first time that the phosphorylated tau in model hippocampus, accompanied by increased mitochondria transport, was mediated by CRH receptor1, not by glucocorticoid receptor, which suggested that centrally derived CRH may be involved in the process of mitochondria axon transport and hence play an important role in the pathogenesis of depression.
为验证该假设,我们首先建立了母子剥夺抑郁模型,对其进行了行为学测试,并检测了HPA轴活性。然后检测了海马中tau蛋白的磷酸化水平。为了研究轴浆运输的变化,我们选择了检测海马突触体中线粒体水平的变化。结合CRH(Corticotropin-Releasing Hormone,CRH)受体1(CRH Receptor1,CRHR1)和糖皮质激素受体(Glucocorticoid Receptor,GR)的拮抗剂,研究了CRH直接的中枢作用机制和HPA轴的反馈机制在tau蛋白磷酸化和线粒体运输中的作用,。为了进一步检测tau蛋白磷酸化和线粒体运输的关系,我们用实时成像技术,观察当原代神经元中tau蛋白磷酸化水平发生变化时线粒体运输的动态变化。结果发现:
1.母子剥夺抑郁模型具有典型的抑郁样行为和过度激活的HPA轴。
在旷场、糖水偏好和明暗箱行为学测试中,抑郁模型具有典型的抑郁样行为。和对照组相比,抑郁模型具有显著升高的血浆cortitosterone和下丘脑CRH mRNA水平。
2.抑郁模型海马中tau蛋白的磷酸化水平显著升高。
和对照组相比,抑郁鼠的海马中tau蛋白的总表达水平没有显著变化,但在在AT-8磷酸化位点显著升高,在tau-1非磷酸化位点显著降低。
3.抑郁模型海马突触体中的线粒体水平显著升高。
和对照组相比,抑郁模型海马突触体中的线粒体水平显著升高。
4. CRHR1而不是GR介导了tau蛋白的磷酸化水平升高和突触体中线粒体水平的升高。
CRHR1的拮抗剂CP154526能显著降低tau蛋白的磷酸化,并能恢复突触体中线粒体的水平,而GR的拮抗剂RU486却没有这些作用。
5.在原代神经元中,当tau蛋白磷酸化水平降低时,线粒体的轴浆运输水平下调。我们用锂盐抑制Gsk3beta的活性从而降低原代神经元中tau蛋白的磷酸化水
平,我们观察到线粒体的轴浆运输水平显著下降。
上述结果表明,在抑郁模型中CRHR1介导了tau蛋白的过度磷酸化,同时伴随着突触体中线粒体水平的升高。这向我们揭示,在抑郁模型中,CRH的中枢作用参与了线粒体运输的调控,这可能为研究抑郁发病机制提出了一条新思路。
Corticotropin-releasing hormone (CRH) is considered as the driving force for hypothalamo-pituitary-adrenal (HPA) axis and play an important role in mood regulation. HPA axis is reported to be closely related to acute stress induced tau phosphorylation in rodent hippocampus. However, the relationship between the hyperactive HPA axis and tau phosphorylation in hippocampus and hence the functional implications in depression are not fully understood. In the present study, we aimed to examine the tau phosphorylation and the effect on axon transport of mitochondria in hippocampus of a depression model. A mice depression model was made by neonatal isolation before weaning, followed by chronic mild stress by social isolation after weaning. Behavior tests showed that the model had a typical depression-like behavior accompanied by increased plasma corticosterone level and hypothalamic CRH mRNA expression. The phosphorylated tau increased significantly, accompanied by increased synaptosome mitochondria level in hippocampus of the depression model. CRH receptor1 antagonist (CP154 526) treatment, not glucocorticoid receptor antagonist (RU486) treatment, decreased tau phosphorylation level, and restored synaptosome mitochondria level in model hippocampus. Moreover, when hyperphosphorylated tau was inhibited by lithium, the mitochondria transport monitored by live imaging was decreased in cultured primary hippocampus neuron. We showed here for the first time that the phosphorylated tau in model hippocampus, accompanied by increased mitochondria transport, was mediated by CRH receptor1, not by glucocorticoid receptor, which suggested that centrally derived CRH may be involved in the process of mitochondria axon transport and hence play an important role in the pathogenesis of depression.
引文
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