Cdk5 and JNK Cascade in Alzheimer’s Disease

Previous studies have shown that the inhibition of JNK pathway using CEP-1347 (Cephalon) or SP600125 prevents neuronal cell death in in vivo models of AD, prompting pharmaceutical companies to direct their attention towards treatment of AD using specific JNK inhibitors. We identified Cdk5 as an upstream regulator of JNK cascade, inhibition of which abrogates JNK cascade. Most importantly, c-Jun, which is the key JNK effector that promotes neurodegeneration, was identified to be directly regulated by Cdk5, suggesting that JNK inhibition alone would not prevent neurotoxicity. These results were further confirmed in vivo using AD mouse models. These results revealed that Cdk5 inhibition is more neuroprotective than either JNK or c-Jun inhibition in AD.