Cdk5 is a major regulator of p38 cascade: relevance to neurotoxicity in Alzheimer's disease.

Cyclin-dependent kinase (Cdk) 5 and p38 activities are significantly increased in Alzheimer's Disease (AD). Both p38 and Cdk5 promote neurodegeneration upon deregulation. However, to date the mechanistic link between Cdk5 and p38 remains unclear. This study presents the first mechanism showing Cdk5 as a major regulator of p38 cascade in neurons and in transgenic mouse model of AD. Using beta-amyloid and glutamate as the neurotoxic stimuli, our results show that deregulated Cdk5 induces p38 activation by increasing reactive oxygen species (ROS) in neuronal cells and in primary cortical neurons. Elimination of ROS inhibits p38 activation, revealing ROS as major stimuli of the p38 cascade. Importantly, Cdk5-mediated p38 activation increases c-Jun expression, thereby revealing a mechanistic link between deregulated Cdk5 and c-Jun level in AD brains. c-Jun is over-expressed in AD, and is believed to contribute significantly to neurodegeneration. Based on the proposed mechanism, Cdk5 inhibition is more neuroprotective relative to p38 and c-Jun, suggesting that Cdk5 is an upstream regulator of neurodegenerative pathways triggered by p38 and a preferable therapeutic target for AD.