DAla2GIP-Glu-PAL对阿尔茨海默病APP/PS1转基因鼠的神经保护效应研究

项目名称： DAla2GIP-Glu-PAL对阿尔茨海默病APP/PS1转基因鼠的神经保护效应研究

项目编号： No.31471080

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 神经、认识与心理学

项目作者： 祁金顺

作者单位： 山西医科大学

项目金额： 81万元

中文摘要： 阿尔茨海默病（AD）是导致老年人寿命降低和生活质量下降的主要疾病，目前仍缺乏有效治疗措施。研究表明，Ⅱ型糖尿病是AD重要的危险因素，肠促胰岛素（GIP）可以通过血脑屏障进入脑内，调节胰岛素信号、促进神经再生，但其生物半衰期很短，不能用于AD的长期治疗。DAla2GIP-Glu-PAL是最新设计的GIP类似物，可免受二肽酶Ⅳ裂解，使半衰期大大延长。然而，DAla2GIP-Glu-PAL的在体神经保护作用特别是抗AD效应还未见研究报道。本研究将利用APP/PS1转基因小鼠，结合行为、电生理、分子生物及非损伤微测定技术，系统观察DAla2GIP-Glu-PAL是否能够有效逆转AD小鼠病理性脑损伤及认知功能伤害，并通过检测在体海马场电位、跨膜离子电流、炎性反应因子和相关信号转导通路，阐明DAla2GIP-Glu-PAL神经保护作用的可能机制，为AD治疗寻找新的突破点。

中文关键词： 阿尔茨海默病；APP/PS1转基因鼠；DAla2GIP-Glu-PAL；学习记忆；突触可塑性

英文摘要： Alzheimer's disease (AD) is the most common type of dementia, which seriously affects the life quality of the elderly, but no effective treatment is found up to now. Epidemiological studies have shown that type 2 diabetes mellitus is an important risk factor of AD, and the both diseases show the common impairments in central insulin receptor and its signal transduction. It is reported that Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, plays an important role in memory formation, synaptic plasticity and cell proliferation. However, GIP is quickly degraded by the enzyme dipeptidyl peptidase IV, and the half-life of GIP is less than 2 minutes, which is nearly useless for the long-term treatment of AD. DAla2GIP-Glu-PAL is a newly synthetic novel enzyme-resistant GIP analogue, with 5-6h of longer half-life, but the neuroprotective roles of DAla2GIP-Glu-PAL especially its anti-AD effects are still not reported up to now. The present study will test the neuroprotective effects of DAla2GIP-Glu-PAL against the cerebral pathological impairments and cognitive deficits in APP/PS1 transgenic mice. Further, the cellular and molecular mechanisms of DAla2GIP-Glu-PAL will be examined by recording in vivo hippocampal field potential, brain slice ion channel currents, and cerebral inflammatory factors in the brain. The study will try to provide a novel and effective strategy for the treatment of neurodegenerative diseases such as AD.

英文关键词： Alzheimer's disease;APP/PS1 transgenic mouse;DAla2GIP-Glu-PAL;Learning and memory;Synaptic plasticity