糖基化终产物致糖尿病认知障碍: BDNF-TrkB-CREB信号介导的海马重塑神经网络机制研究

Hippocampal neurogenesis can remodel the formation of neural network and promote cognitive rehabilitation under the disease status. The molecular mechanism and functional significance are two major difficulties in this field. Humans with poorly controlled diabetes show hyperglycemia accompanied by an accelerated rate of advanced glycation end products (AGEs) formation and accumulation. An intriguing property of the adult hippocampus is its capability to generate new neurons throughout life, and this property contributes to functional plasticity under both physiological and pathological conditions. Hippocampal neurogenesis is hypothesized to be an etiological factor of cognitive or depressive diseases. Our previous findings provided in vivo and in vitro evidences that diabetes impairs hippocampal function via the AGEs-mediated decreased generation of new neurons from neural progenitor cells (NPCs), including NPCs proliferation and their neuronal differentiation. BDNF-TrkB-CREB pathway plays key roles in this process. The current study will focus on this pathway and the ploymorism of BDNF gene Val66Met and is designed to further elucidate the mechanism and function of AEGs-related neurogenesis deficit, using multi-modal MR imaging and genomicimaging techniques. The findings may contribute to the onset of diabetes-related cognitive decline and thus represents a potential target for therapy.

海马重塑可促进疾病状态下神经网络的形成和认知功能康复，其分子机制及功能意义是该领域研究的两大难点。本研究正基于此，在前期系列研究取得实质性进展，并发现海马重塑可能介导糖毒性效应分子糖基化终末产物 (AGEs)致糖尿病认知障碍基础上，继以AGEs对海马重塑及其神经网络影响为突破口，紧紧围绕BDNF-TrkB-CREB信号通路及BDNF(Val66Met)基因多态性，发挥现已有跨学科交叉集成优势，多层面深入探讨该信号通路介导AGEs致糖尿病认知障碍的海马重塑神经网络机制, 并联合运用多模态神经影像技术，在体水平进一步揭示其临床功能意义，以期最终发现糖尿病认知障碍的分子和影像学标记，对完善临床诊疗策略进行创建性的探索。本研究必将为探讨糖尿病状态下高级神经活动－情感障碍的分子机制提供新的思路和证据。

海马重塑可促进疾病状态下神经网络的形成和认知功能康复，脑影像学分析技术的发展为探索糖尿病的脑部变化提供了契机。本研究正基于此，在前期系列研究取得实质性进展，并发现海马重塑可能介导糖毒性效应分子糖基化终末产物 (AGEs)致糖尿病认知障碍基础上，继以AGEs对海马重塑及其神经网络影响为突破口，围绕BDNF-TrkB-CREB信号通路及BDNF(Val66 Met)基因多态性，运用多模态静息态fMRI图像分析技术，分别从全脑自发活动水平的程度及脑部不同脑区的功能连通性方面，将临床各项指标与先进的fMRI数据处理算法相结合，为糖尿病状态下高级神经活动－情感障碍的分子机制提供新的思路和证据，为早期识别和治疗糖尿病认知障碍提供新的实验依据。通过本课题的研究将有助于从结构和功能的角度综合分析糖尿病认知障碍发生的神经网络特征和危险基因相关致病因素，进一步促进我们对糖尿病认知障碍神经机制的认识，或有可能成为早期诊断糖尿病认知障碍的客观指标，进而有利于疾病的早期干预。