Alzheimer病脑内BDNF/TrkB信号时空特异性调控LIMK1蛋白并保护突触功能的机制及应用

Alzheimer’s disease is the most common form of dementia in old people. The cause for most Alzheimer’s cases is still mostly unknown and there is no cure for the disease. Hence, it is very important to study the pathogenesis of this disease and to explore the effective drugs. There is evidence that the abnormal levels of brain-derived neurotrophic factor (BDNF) and its TrkB receptor are closely related to the occurrence of Alzheimer’s disease. The impairment of cognition in the early stages of Alzheimer’s disease is associated with deficiency of synaptic plasticity. LIMK1/cofilin signaling plays a direct role in regulating actin reorganization and modulating synaptic plasticity. However, it is still unknown whether LIMK1/cofilin signaling participates in the occurrence of Alzheimer’s disease. In our previous study, we demonstrated that there is interplay between TrkB and LIMK1; in addition, BDNF/TrkB signaling directly regulates LIMK1/cofilin signaling and controlling actin reorganization accordingly. Nevertheless, how does BDNF/TrkB signaling regulate LIMK1/cofilin signaling and synaptic plasticity in the process of the Alzheimer’s disease is not clear yet. Adopting molecular methods and behavioral approach, we determine to further explore the mechanism by which BDNF/TrkB signaling temporally and spatially regulate LIMK1/cofilin signaling and protect synaptic plasticity and learning and memory in Alzheimer’s disease, on this basis, we plan to search for new drugs for Alzheimer’s disease. This project is conducive to both the further knowledge of the pathogenesis of Alzheimer’s disease and the search for therapy of Alzheimer’s disease.

Alzheimer病是老年人痴呆中最常见的类型，该发病机制尚不清楚，也无特效的治疗药物，因此研究该病发病机制并探索有效的治疗药物具有重要的意义。研究表明BDNF及其TrkB受体水平的异常与该病的发生有关。该病患者早期出现轻度认知功能障碍与其脑内突触可塑性的缺陷密切相关，LIMK1/cofilin信号可直接调控肌动蛋白重组而参与调节突触可塑性。我们的研究发现TrkB和LIMK1之间存在相互作用，BDNF/TrkB信号可直接调控LIMK1蛋白活性，而在Alzheimer病脑内BDNF/TrkB信号如何调控LIMK1信号而影响突触可塑性的机制尚不明确。本项目将深入探索Alzheimer病脑内BDNF/TrkB信号如何时空特异性的调控LIMK1信号从而保护突触可塑性的分子机制，并在此基础上探寻治疗该病的新药物。本项研究有利于深入理解Alzheimer病的发病机制，并为该病的治疗提供新的依据。

阿尔茨海默病（Alzheimer’s dementia, AD）是老年人中最常见的痴呆，是由于脑内β淀粉样蛋白的沉积及神经元纤维的缠结所致，但目前尚无特效的治疗方法。因此，深入探索AD的发病机制及寻找有效的治疗药物具有重要的意义。近些年来，越来越多的证据表明AD与2型糖尿病（Type 2 diabetes mellitus, T2DM）之间可能存在很多关联，阿尔兹海默病甚至被认为是3型糖尿病。通过脑内侧脑室内注射的方法给与Aβ寡聚体，从而建立AD大鼠模型，我们发现通过这种方法可引起脑内淀粉样物质的沉积并出现大鼠认知功能的下降，但此方法建模周期长，模型相对不够稳定，重复性欠佳等，从而影响后续实验结果，因此，最后我们考虑用APP/PS1转基因小鼠模型作为研究对象，探索西格列汀口服对AD小鼠具有脑保护作用以及他的作用机制。我们用降糖药DPP-4抑制剂西格列汀处理7月大和9月大的AD转基因小鼠各2个月，然后进行水迷宫实验及旷场实验等，发现西格列汀对AD早期小鼠的学习记忆能力具有保护作用，对晚期AD小鼠无效。因此我们进一步研究西格列汀对AD早期小鼠发挥脑保护作用的分子机制。西格列汀处理2月后，分别检测海马中的淀粉样物质的沉积、树突棘数目的变化、突触体中AMPA受体数目的变化及BDNF/TrkB的表达，发现西格列汀可减少海马区淀粉样物质的沉积，同时海马中BDNF/TrkB信号的表达、突触后AMPA受体的含量及树突棘的数目均较生理盐水对照组明显增加。分别抑制GLP1和GIP信号及Trk信号，发现西格列汀的脑保护作用被GLP1抑制剂及Trk信号抑制剂k252a所抑制。以上结果表明，DPP-4抑制剂可通过GLP信号及BDNF/TrkB信号作用于脑内，增强脑内的突触可塑性，发挥对AD小鼠的脑保护作用。这一结果进一步证实了糖尿病和AD之间有一定的联系，为临床医生做出临床用药决策提供一定的理论依据，西格列汀适用于糖尿病伴或不伴有AD的患者，尤其适合糖尿病合并早期AD的患者。

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