The role of Pax6 in Beta-Amyloid toxicity and Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a progressive neurological disorder which is characterized by the neuronal dysfunction and loss in the patient brain. Previous studies has shown that cell cycle components such as Cyclin dependent kinase 4(CDK4), pRb and transcription factor E2F1/DP-1/C-Myb play critical roles in various models of AD. However, the mechanism by which cell cycle proteins regulate neuronal loss, especially the downstream events of this pathway are largely unknown. In this study, we identified a novel E2F1/C-Myb target gene Pax6, 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)( A􀈕1-42) treatment.We found that siRNA-mediated knockdown of Pax6 protects cultured mouse cortical neurons from A􀈕1-42 induced neuronal death. Also we found that Pax6 mRNA/protein levels and transcriptional activity increase with A􀈕1-42 treatment in neurons and in APP mutant cell lines.We also showed that the endogenous induction of Pax6 by A􀈕1-42 treatment can be significantly blocked by the CDK4 inhibitors and Pax6 might be a target gene of CDK4/E2F1/C-Myb related cell cycle apoptosis pathway in this death model. Moreover, Pax6 is elevated in cortical neurons of entorhinal cortex, a brain region affected by AD, in an APP transgenic mouse model. Taken together, Pax6 is required for A􀈕1-42 induced neuronal apoptosis and play an important role in Alzheimer’s disease pathogenesis. This study may provide insights into development of therapeutic agents and approaches for AD through inhibition of Pax6 which has lower expression in normal adult brain.