阿尔茨海默病（AD）是一种严重影响人类健康的神经退行性疾病。导致AD发病的最终原因是神经元的死亡丢失。因此充分理解AD致病过程中神经元凋亡的机制对于AD 的防治十分重要。细胞周期蛋白激酶5（Cdk5）（P35-Cdk5）对维持正常神经生理功能具有重要的作用，而其异常的激活(P25-Cdk5)直接参与了AD的发生发展，但对于P35-Cdk5和P25-Cdk5的神经功能差别研究还很缺乏。我们使用磷酸化蛋白质组学鉴定出了Bag3是P25-Cdk5，而不是P35-Cdk5的底物。P25-Cdk5 对Bag3 的磷酸化调控了神经元的突触传递和凋亡。 因此Bag3可能是Cdk5功能转变的关键点。我们将使用定制的pBag3 磷酸化抗体，bag3-/-,cdk5-/-,AD 等小鼠模型研究P25-Cdk5 对Bag3 磷酸化修饰后对神经突触功能和神经元凋亡的影响和机制, 为寻找治疗AD新的靶点提供依据。

Alzheimer's disease (AD) is an non-curable, severe neuronal degeneration disease. The final reason for the pathogenesis of AD is the neuronal death and loss. Thus the investigation of the neuronal death mechanism during AD pathogenesis is vital for the prevention and curing of AD. The activation of Cyclin Dependent Kinase 5(Cdk5) by P35(P35-Cdk5) is vital for maintain the normal neuronal function, the atypical activation by the cleavage truncation of P35: P25(P25-Cdk5) is correlated with the pathogenesis of Alzheimer’s disease (AD). Less reports have been addressed to investigate the functional pathway variation between Cdk5-P35 and Cdk5-P25. We recently identified Bag3 (Bcl-2-associated athanogene 3) is a specific target of P25-Cdk5, but cannot be phosphorylated by P35-Cdk5. We then identified the phosphorylation site of Bag3 by P25-Cdk5, and custom-made a specific phospho-antibody which can recognize the phosphorylation of Bag3. We then found that the phosphorylation of Bag3 is correlated with the dysfunction of synaptic transmission and neuronal death which is dramatically effect by P25-Cdk5. Thus, Bag3 may be the key protein for the switch of normal Cdk5 function to disease related function. By using phospho-Bag3 antibody, bag3-/-, cdk5-/-, AD mice models, we will investigate the phosphorylation modification of Bag3 by Cdk5, and its’ effects on neuronal synaptic function and neuronal death. The current research will benefit us to understand the detailed mechanism of P25-Cdk5 induced neuronal dysfunction and provide new pharmatheutical target for prevention and cure of AD.