早期AD中LTD的受体及细胞内信号机制研究

The prevalence of Alzheimer's Disease is increasing dramatically with the acceleration of the population aging，but the etiology and pathogenesis of AD remains unclear, and there is not clinically effective treatment. So the research on mechanism, diagnosis and treatment in the early stage are especially important. The modulation of the synaptic plasticity mediated by Aβ is an important role in the early lesions. Most of the studies focus on LTP but a few on LTD where the mechanism is unclear. In present project, the mechanism of LTD in the early AD will be investigated in the different ages of AD transgenic animals and control animals by the methods of electrophysiology, behavior, biochemistry and molecular biology, morphology, focused on the role of glutamate receptors, the difference between mGlu and NMDA receptors, the role of different subtypes of these receptors. Further research will be carried on the intracellular signaling pathways, specially on Caspase, p38MAPK, STEP and mTOR, try to find the mechanism of Aβ-mediated LTD enhancement in early AD and provide more accurate theoretical basis for early AD diagnosis and treatment.

随着社会老龄化的加快，阿尔茨海默症的患病率正急剧增加。目前AD 的病因学和发病机制依然不清楚，临床上也无有效的治疗方法, 因此其早期的机制研究、诊断及治疗尤其显得重要。Aβ介导的突触可塑性变化是其早期病变的重要原因， 其中LTP的研究相对较多，而对LTD的研究较少，机制不甚清楚。本课题中，应用电生理学、行为学、生物化学与分子生物学、形态学等技术，分别在不同月龄的转基因AD模型动物及对照动物上，探讨早期AD中Aβ介导的LTD增强作用的细胞膜上及细胞内机制，着重研究谷氨酸受体的作用，比较mGlu与NMDA 受体的区别，研究不同受体亚型的作用；并进一步探讨细胞内参与的信号途径，特别研究Caspase、p38MAPK、mTOR 及STEP 等细胞内信号系统的作用，从而明确Aβ介导的LTD增强在AD 早期病理机制中的作用和相关机制，为早期AD 诊断和治疗提供更精确的理论依据。