ADAM10在皮层神经元放射状迁移中的作用与机制

Alzheimer's disease (AD) is one the three popular neurodegenerative diseases, and still requires better strategies for diagnosis and therapy. Early diagnosis and therapy is an important direction for this improvement. Recently, several AD-related genes such as amyloid protein precursor (APP) and presenilins were found to play critical roles in the development of the central nervous system, which expand our understanding of the neural development basis of AD on-set, thereby providing important clues for the investigation of early pathological changes that lead to AD. Our preliminary result implies an essential role of ADAM10, a metalloprotease that related to AD, in the biogenesis especially radial migration of the cerebral cortex. To further investigate the function and the underlying mechanisms of ADAM10 in cortical radial migration, we will study the in vivo subcellular localization of ADAM10, the role and its underlying cellular and molecular mechanisms of ADAM10 in cortical radial migration through combined approaches of molecular biology, immunofluorescent staining, imaging and in utero embryo electroporation. This work will not only expand our understanding of the function of ADAM10 in the brain, but also increase our knowledge of the molecular mechanism of corticogenesis, which will provide important scientific fundamentals for the development of new strategies for AD diagnosis and therapy, especially drug discovery targeting to ADAM10.

阿尔兹海默氏症是三大神经退行性疾病之一，目前仍急需有效的诊疗方法。早期诊断和治疗是提高诊疗效果的重要方向。现有研究表明APP, Presenilins等AD相关分子在神经发育过程中发挥重要作用，为探索AD疾病的神经发育基础并进而了解AD早期病变机制提供了新的重要线索。我们初步数据表明AD相关基因ADAM10可能是调控皮层发育特别是放射状迁移的重要因子。为了深入阐明ADAM10在皮层放射状迁移中的作用与机制，我们拟采用分子生物学、形态学和胚胎电转等方法深入研究ADAM10分子的亚细胞定位情况，以及ADAM10调控迁移的细胞学和分子生物学机制。本研究将不仅拓展我们对ADAM10功能的了解，还将丰富我们对皮层发育机制的认识，并为AD的诊疗包括针对ADAM10的药物筛选提供重要的科学依据。

神经元迁移需要多种膜信号感受与转导机制来应对周围环境、控制内部信号事件。受调控的膜剪切（RIP）作为一种重要的膜信号范式，其在神经元迁移中的具体作用与机制研究尚不清楚。本着这一出发点，我们选择ADAM10作为切入点。我们发现ADAM10起始的RIP能够促发膜上的Notch分子释放NICD，后者进入细胞核内，调控微管结合蛋白DCX和FGF13b的表达，进而影响微管稳定性，调控神经元迁移。本项目揭示了RIP作为膜信号转导范式对神经元迁移是重要的，是调控迁移的新信号机制，填补了理论空白。同时，本项目将ADAM10/Notch这一RIP事件与微观稳定性直接联系起来，阐述了一个重要的分子机制，其不仅有助于理解神经元迁移的分子机制，也对所有微管参与的细胞运动、形态变化事件的理解提供新的科学参考。