大脑中神经元缺失是阿尔茨海默症(AD)的一个重要特征。细胞周期相关分子-CDK4/pRb/E2F1等，在AD病变中，均起关键作用。 但其调控神经元凋亡的机制，特别是该通路下游调控，尚不清楚。我们的先期实验首次发现了在Aβ1-42诱导凋亡的小鼠胚胎皮层神经元中，C-myb和Pax6的mRNA、蛋白质水平以及转录活性均随着Aβ诱导而增加。如沉默Pax6或c-Myb的表达则保护皮层神经元，抵制Aβ对神经元的死亡诱导作用。E2F1和C-myb均可与Pax6的启动子区域结合。虽然Pax6已知在大脑、眼等发育中是一个重要的转录因子，Pax6 却是一个E2F1的新下游靶点起着重要作用。为证实这一新机制，我们将用Pax6突变小鼠和AD模型及分子和细胞技术究研这一新的通路；同时用RNA-seq先期结果发现pax6 新的下游靶点。这项研究可能为AD的治疗药物的开发提供新的思路，即抑制Pax6在AD中的表达。

Alzheimer's disease (AD) is a progressive neurological disorder which is characterized by the neuronal dysfunction and loss in AD brain. Previous studies has shown that cell cycle components such as Cyclin dependent kinase 4 (Cdk4), pRb and transcription factor E2F1 play critical roles in various models of AD. However, the mechanisms by which cell cycle proteins regulate neuronal loss, especially the downstream events of this pathway, are largely unknown. In this study, we, for the first time, identified a novel E2F1 target gene Pax6 although it is known as a key transcription factor essential for the development of brain, eye and pancreas, as an important regulator of neuronal cell death evoked by Beta-amyloid (1-42) (Aβ1-42) treatment. Our preliminary data showed that, in murine embryonic cortical neurons, C-myb mRNA/protein levels，Pax6 mRNA/protein levels and transcription activity, increase with Aβ treatment. We also found that siRNA-mediated knockdown of Pax6 or C-myb protects neurons from Aβ induced neuronal death. Both E2F1 and C-myb can interact with Pax6 promoter region. We hypothesize that C-myb and Pax6 regulate downstream of cell cycle pathway, and are directly regulated by transcription factor E2F1. C-myb and Pax6 maybe required for Aβ induced neuronal apoptosis and play an important role in AD pathogenesis. We plan to use pax6 deficient mice/AD transgenic mouse modes to test this hypothesis in vivo and explore putative mechanism of C-myb and Pax6 involved in cell cycle mediated neuronal death pathway. Furthermore, based on our RNA-seq data of Pax6 silence in AD neurons, we shall assess the function of downstream novel targets of Pax6 in AD models. This study may provide insights into development of therapeutic agents and approaches for AD through inhibition of Pax6 in AD brain.