经颅磁刺激对 Alzheimer病小鼠脑内homer1a-BK channel信号通路的影响及疗效评估

细胞内Aβ是AD发病的最上游机制之一。胞内Aβ通过抑制BK channel（BK）功能发挥毒性作用。研究证实，Homer1a是解除BK 功能抑制的关键因子。电休克能诱发AD鼠脑homer1a增加而活化BK。但电休克临床可行性差。我们发现经颅磁刺激（rTMS）可诱导抑郁症小鼠脑homer1a增加。rTMS无创，临床适用性强。rTMS对AD小鼠脑homer1a及BK的影响迄今并无相关研究。我们推测：若将rTMS用于AD治疗，rTMS可通过诱导homer1a增加，解除BK功能抑制,阻断AD发病的最上游机制，效果值得期待。rTMS治疗AD的临床研究以及预实验结果为本实验思路提供了佐证。本课题拟用rTMS刺激AD小鼠，多方面研究homer1a及BK功能变化，并用homer1a敲除小鼠进行验证，另对老年AD小鼠进行rTMS以更贴近临床。本研究可为AD的机制性治疗提供靶点，为AD治疗药物的研发提供思路。

The producing of intracellular soluble Aβis one of the most upstream mechanism in the pathogenesis of AD. The intracellular soluble Aβplays a toxic role by inhibiting the function of BK channel. Studies confirmed that Homer1a is the key factor to lift the suppression of BK channel function. Electric shock can increase homer1a expression and activate BK channel in AD mice brains. But the application of electric shock in clinical treatment is infeasible. We found that transcranial magnetic stimulation (rTMS) can increase homer1a expression in the brain of depression mice. The rTMS is noninvasive thus has good clinical applicability. There is no report on the impact of rTMS on the expression of homer1a and its action on the function of BK channel in the brain of AD mice. We proposed: If the rTMS is used to treat AD mice, rTMS may lift the suppression of BK channel function by inducing the expression of homer1a, thereby block the most upstream mechanism of AD pathogenesis. The effect of rTMS is expectable. Clinical studies of rTMS treatment on AD and results of preliminary experiments provided strong evidence to support our proposal. This project intends to use rTMS on AD mice to study the expression of homer1a and the changes of BK channel function from various aspects, the homer1a knockout AD mice will be used to verify this idea. To recapitulate the clinical practice, old AD mice will be used to test the therapeutic effect of rTMS treatment. This study will provide important implications for the treatment of AD and give new ideas for drug development of AD.