Role of CDK5/Id1/HIF-1 in Neuronal Cell Cycle Re-entry Induced by Amyloid-Beta Peptide

• Main Authors: Chien-Hui Chen, 陳芊慧
• Other Authors: Dean-I Yang
• Format: Others
• Language: zh-TW
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/4wt5yv

碩士 === 國立陽明大學 === 腦科學研究所 === 105 === 　　Alzheimer’s disease (AD) is characterized by accumulation of senile plaques mainly composed of neurotoxic amyloid beta-peptide (A), which may lead to neuronal cell cycle re-entry. Cyclin-dependent kinase-5 (CDK5) deregulation contributes to the re-activation of cell cycle events in several neurodegenerative diseases including AD. In the brains of AD　patients, the truncated fragment of the normal CDK5 regulator p35, p25, has been found to accumulate in the neurons. The p25/Cdk5 complex induces cytoskeletal disruption, morphological degeneration and apoptosis. We have demonstrated A–induced inhibitor of differentiation-1 (Id1) and hypoxia-inducible factor-1 (HIF-1) in cortical neurons. The p25/Cdk5 complex is also known to be induced by A. However, whether the A-induced CDK5 regulates Id1/HIF-1 induction with resultant cell cycle re-entry remains unknown. In the present study, we found that A induced expression of p25 known to cause hyper-activation of CDK5 in cultured cortical neurons. A–induced HIF-1 and cyclin D1, the latter being a G1 phase marker during cell cycle progression, were both inhibited by CDK5 inhibitor roscovitine. The HIF-1 siRNA attenuated Ab-induced cyclin D1 expression. The Id1 siRNA enhanced expression of both Ab-induced and endogenous p25. Exogenous Id1-tag capable of direct cell membrane penetration suppressed p25 expression independent of A. Whether direct activation of p25/CDK5 independent of A is sufficient to repress Id1 expression in rat cortical neurons requires further investigation. In conclusion, these experimental results appear to support the contention that A–induced HIF-1 is regulated by CDK5 based on its inhibitor roscovitine, thereby resulting in cell cycle re-entry in post-mitotic neurons as evidenced by the increased expression of cyclin D1. Furthermore, A enhances the expression of both Id1 and p25, whereas these two proteins appear to suppress the expression of each other, both with and without the presence of A.