阿尔茨海默病（AD）是一种严重影响人类健康、不可治愈的神经退行性疾病,因此对AD早期病变的研究就格外重要。由神经元细胞周期紊乱所导致的细胞凋亡是AD中已知最早的病理变化，但对其机制还不清楚。我们第一次发现Cdk5具有抑制神经元细胞周期的功能，并于近期鉴定出了Cdk5两个新底物：FOXO1和CEND1，他们和细胞周期、凋亡都密切相关。本课题中我们将应用细胞周期和细胞凋亡实时检测系统、胚胎子宫电穿孔技术在原代神经元、AD小鼠、细胞周期小鼠模型中研究Cdk5对FOXO1、CEND1的调控机制及其对神经元细胞周期的影响。我们还将应用上述模型和方法研究神经元细胞周期紊乱和细胞凋亡的时程关系，及其在AD致病过程中的关联。通过对以上内容的研究，我们期望能更加深入了解AD致病过程中细胞周期紊乱所导致的凋亡过程，为预防和治疗AD提供更多的理论基础和作用靶点。

Alzheimer's disease (AD) is an non-curable, severe neuronal degeneration disease. Thus the investigation on earlier pathological dysfunction of AD is vital for the disease prevention. The neuronal cell cycle re-activation is the earliest dysfunction has been found in AD till now. For the first time, we found that Cdk5(Cycling dependent kinase 5) works as neuronal cell cycle suppressor in post-mitotic neuron, but the detailed mechanism is not fully understood. We receatly identified two new substrates of Cdk5: FOXO1 and CEND1. These two proteins are closely related with the cell cycle and cell death pathway. In the current proposal, The cell cycle monitoring system, cell death monitoring system, in utero electroporation will be used, and primary neuron culture, AD mouse model, cell cycle mouse model will also be invovled in this project. We will investigate the effect of Cdk5 on FOXO1 and CEND1, and their involvment in neuronal cell cycle regulation. At the same time, the timing correlation between neuronal cell cycle dysfunction with neuronal apoptosis and the AD pathology progression will also be investigated by the above methods and models. The current research will benefit us to understand the detailed mechanism of neuronal cell cycle dysfunction and its correlation with cell death, and provide new pharmatheutical target for prevention and cure of AD.