应激水平的糖皮质激素（GC）对海马神经元具有损伤作用，与老年性痴呆的发病密切相关。GC可损伤动物的学习记忆功能，促进钙离子内流而增加NMDA的神经毒性，增加神经元ROS生成，增加Caspase3活性，促进Aβ对神经元的毒性和损伤。我们预实验发现，GC能明显激活BK通道，促进钾离子外流，而ROS增加和细胞内低钾可以激活炎症小体。据此我们提出慢性应激水平GC可以上调和激活NLRP-1炎症小体导致海马神经元损伤的假说。本研究利用膜片钳、免疫荧光、蛋白印迹、免疫共沉淀、定量PCR、激光共聚焦等技术：①用野生和NLRP-1敲除小鼠研究GC对NLRP-1的调节作用及对海马神经元的损伤作用及机制；②研究GC对海马神经元BK通道的调节及对NLRP-1激活的影响；③研究NLRP-1炎症小体在慢性应激水平GC致海马神经元损伤中的作用及其机制。期望为防治大剂量GC应用和慢性应激对神经元的损伤提供新思路和新靶点。

Alzheimer's disease (AD) is a chronic neurodegenerative disorder marked by a progressive loss of memory and cognitive function. Plasma stress level glucocorticoids (GCs) are correlated with dementia progression in patients with AD. It is reported that GCs can enhance NMDA neurotoxicity through facilitating [Ca2+](i) increment and attenuating the NR2A-ERK1/2-mediated neuroprotective signaling. GCs can reduce hippocampal dendritic complexity and can even cause hippocampal cells death. Our previous studies showed that twenty one days exposure of dexamethasone (DEX) induced impairment of memory and learning, accompanied by severe histological damage in the hippocampus in senescent mice. Furthermore, DEX treatment increased ROS production and the activity of caspase-3, facilitated Aβ25-35 neuronal cytotoxicity and induced cortex and hippocampus neurons apoptosis. Our preliminary experiment showed that DEX significantly activated BK ion channel and enhanced K+ efflux.While the ROS accumulation and K+ efflux can activate the NLRP-1 inflammsome. So we hypothesize that chronic stress level of GCs may upregulate and activate NLRP-1 inflammsome in hippocampal neurons, which may be related with the GCs induced hippocampal injury. In this study, patch clamp, immunofluorescence, immunoblotting,co-immunoprecipitation, Real time PCR, confocal microscopy and flow cytometry will be used to tudy the effects and mechanisms of stress level of GCs on neurodegeneration. ① The effects and mechanisms of stress level of GCs on the regulation of NLRP-1 inflummsome in hippocampal neurons in wild and NLRP-1 knock-out mice. ② The effects and mechanisms of stress level of GCs on regulation of BK ion channel and activation of NLRP-1inflammsome in hippocampal neurons. ③ The effects and mechanisms of NLRP-1inflammsome on GCs mediated hippocampus neuronal injury.This study will provide new idea and target point for prevention and therapy of large dose GCs and chronic stress induced neurodegeneration.