激活胰岛素信号转导通路干预慢性脑缺血所致的阿尔茨海默样病理改变及认知功能障碍

Chronic cerebral hypoperfusion (CCH) leading to vascular cognitive impairment even vascular dementia immerged to the front edge of neurology research. Several studies proved that CCH participates in the pathogenesis of cognitive dysfunction cooperatively or independently. There are several similarities between the pathogenesis of CCH caused cognitive impairment and Alzheimer’s Diseases, including accelerated Aβ deposition, increased phosphorylation of tau and dysregulated synaptic proteins. Our previous studies found that CCH caused a decrease in O-GlcNAcylation and an increase in tau phosphorylation, dysregulated synaptic proteins, and resulted in alterations of the HBP and insulin signaling pathway in the mouse brains. We still proved that pretreatment with intranasal insulin prevents propofol-induced AD-like tau hyperphosphorylation. Base on all of our previous studies, this project is major in investigating the effect of intranasal insulin on CCH-induced cognitive impairment, alternations of insulin signaling, HBP pathway, O-GlcNAcylation, tau hyperphosphorylation and neuronal degeneration, aiming to discuss the molecular mechanism of activated insulin signaling ameliorates CCH induced Alzheimer’s pathologies and cognitive impairment.

慢性脑缺血导致血管性认知功能障碍甚至血管性痴呆已逐渐成为神经病学领域的研究热点。已有研究证实，慢性脑缺血独立或协同参与了认知功能障碍的发生，且其发生机制与阿尔茨海默病的发病机制有一定相似之处：包括加速Aβ沉积，导致tau蛋白过度磷酸化及突触相关蛋白表达失调等。我们的前期研究发现，单侧颈总动脉结扎术建立的慢性脑缺血小鼠模型脑内O-GlcNAc糖基化水平下调，tau蛋白过度磷酸化，突触相关蛋白调节异常，以及胰岛素信号转导通路代偿性激活。我们还发现，经鼻吸入胰岛素可降低异丙酚诱导的tau蛋白过度磷酸化。本课题基于前期工作基础，进一步研究经鼻吸入胰岛素对于慢性脑缺血动物模型的认知功能、胰岛素信号转导通路、O-GlcNAc糖基化、tau蛋白磷酸化及神经元变性等诸多方面的影响，以探讨激活脑内胰岛素信号转导通路对慢性脑缺血所致的阿尔茨海默样病理改变及认知功能障碍的干预作用及其分子生物学机制。