经颅磁刺激对应激处理阿尔茨海默病模型小鼠抑郁症状的治疗价值及其机制中CDK5相关信号通路作用的研究

阿尔茨海默病是痴呆的主要类型，抑郁是最常见的痴呆非认知表现，对AD患者的病情和预后有加剧恶化的影响，因此治疗抑郁对改善AD非常必要。传统抗抑郁药物对痴呆伴发的抑郁治疗效果欠佳。AD伴发抑郁的机制研究提示，应激状态下HPA轴功能紊乱可通过糖皮质激素影响谷氨酸能信号而引起抑郁，而糖皮质激素受体活性受到CDK5磷酸化作用的调节；另外皮质神经元髓磷脂水平和髓鞘化作用异常可能是抑郁和AD病理机制共同的关键点，而CDK5对髓鞘化过程存在调节作用；我们前期研究发现，经颅磁刺激可易化钙激活依赖性钾离子通道（BK通道）而改善AD症状，而BK通道又在抑郁行为调节中起重要作用，且最近有研究提示BK通道激活与CDK5活性下降有显著关联。据此我们推测CDK5是AD背景上发生抑郁机制中的枢纽性环节，而经颅磁刺激可调节BK通道的活性而影响CDK5相关分子，阻断兴奋性神经递质和神经元髓鞘化作用障碍，达到治疗抑郁的效果。

Alzheimer’ disease is the major type of dementia.，in which syndromes depression is the most common one of non-recognition aspects, creating deterioration of the progression and outcome of AD. Treatment with depression in AD is actually necessary, while the conventional antidepressant drugs seemed inefficiency. The recent data have revealed that HPA axis dysfunction may influence glutamatergic system through modulating glucocorticoid level and lead to depression, during this process the glucocorticoid receptors are modulated by CDK5. Furthermore, myelin/myelination of cortex neurons may be critic in the common mechanism of AD and depression, and CDK5 may regulate myelination. Combined with our previous findings, rTMS could improve AD syndrome by facilitating BK channel, which involves in the modulation of depression related behaviors, and there are recent studies suggest that BK channel activation is associated with CDK5 down-regulation, we postulate that CDK5 plays a pivotal role in the depression on AD background, and rTMS may inhibit CDK5 through BK channel, blocking the excitotoxic glutamatergic transmission and deficits of myelianation in neurons, resulting in improvement of depression.