自噬对记忆和突触可塑性的调控作用和分子机制研究

Alzheimer’s disease (AD) is characterized by memorial and cognitive dysfunction and impairment of synaptic plasticity. Long-term potentiation (LTP) is an important form of synaptic plasticity, and has been regarded as the cellular basis of memory and learning. Autophagy is an important process, which leads to degradation of cellular proteins and organelles by lysosomes for transition cycle of mass and energy. Autophagy is required for tissue development and the maintenance of normal cells homeostasis. Research revealed that disruption of autohagy is involved in the pathogenesis of Alzheimer’s disease. However, the role of autophagy in synaptic plasticity and LTP regulation remains unclear. In our previous study, we generated a mouse model with partial autophagy defects (NRBF2 KO mice). These mice displayed learning and memory defect, impaired LTP expression and decrease of autophagy flux in the central nervous system, but there is no sign of the neurodegeneration. Based on the data, it is reasonable for us to hypothesize that autophagy can directly regulate LTP to affect learning and.memory, and this might be an important mechanism in the pathogenesis of AD. In this project, we will test the hypotheses, and explore the molecular mechanisms how autophagy regulates LTP. Our project will build a direct link between autophagy and LTP, and provide scientific evidence for targeting autophagy as a new strategy to improve the learning and memory symptoms of AD.

记忆和认知功能障碍是阿尔茨海默病（AD）的主要临床表现，同时伴随着神经细胞突触可塑性的下降。长时程增强作用（LTP）是实现突触可塑性的重要生理机制，与记忆的形成密切相关。自噬是细胞通过溶酶体消化自身组分实现物质和能量循环的过程，其正常功能对于维持神经细胞稳态意义重大。研究提示自噬功能的障碍可能参与了AD的病程，然而自噬是否直接影响神经细胞突触功能以及LTP并不清楚。我们在前期研究中建立了一个自噬功能部分缺失的小鼠模型（NRBF2 KO小鼠）。该小鼠表现出部分抑制的神经自噬功能和明显受损的记忆和LTP，但没有任何神经变性的迹象。我们据此假想自噬可以直接调控LTP从而影响记忆，这可能是自噬功能异常参与AD病变过程的一个机制。我们将通过本项目验证此假说，并且探索自噬调控LTP的分子机制。我们的研究将把自噬和LTP这两个重要生理机制联系起来，并且为调控自噬作为改善AD记忆障碍的新策略提供研究基础。

阿尔兹海默病是最常见的神经退行性疾病。研究显示神经细胞内β淀粉样蛋白(Aβ) 毒性是引起突触损伤以及记忆和认知功能障碍的重要病理机制。自噬是细胞通过溶酶体消化自身组分实现物质和能量循环的过程，其正常功能对于维持神经细胞稳态意义重大。研究提示自噬功能的障碍可能参与了AD的病程，然而其分子机制尚未完全被阐明。我们前期研究发现，自噬相关蛋白NRBF2可能参与AD的病变过程。在本项目中，我们在病人脑组织中确认了NRBF2与自噬和AD的密切关系。并发现了NRBF2通作为RAB7的调控因子在自噬的成熟中发挥的重要作用，还揭示了NRBF2-CCZ1-MON1A复合物功对神经元细胞降解APP-CTFs的分子机制。相关研究成果在Autophagy, Theranostics等SCI杂志发表论文9篇，申请中国专利一项。该项目的研究成果为AD的治疗提供新思路。