The complex p25/Cdk5 kinase in neurofibrillary degeneration and neuronal death: the missing link to cell cycle

Emergence of the cell cycle hypothesis in neurodegenerative disease comes from the numerous lines of evidence showing a tight link between "cell cycle-like reactivation" and neuronal death. Terminally differentiated neurons remain in G0 phase and display, compared to proliferating cells, an opposite regulation pattern of cell cycle markers in that most of the key activators and inhibitors are respectively down- and up-regulated. It has been clearly established that any experimental attempt to force terminally differentiated neurons to divide ultimately leads to their death. Conversely, cell cycle blockade in experimental models of neuronal death is able to rescue neurons. Hence, cell cycle deregulation is certainly among mechanisms governing neuronal death. However, many questions remain unresolved, especially those related to which molecular mechanisms trigger cell cycle deregulation and how this deregulation leads to cell death. In the present review, we focus on neurodegeneration in Alzheimer's disease and discuss the cell cycle deregulation related to this neurodegenerative pathology. Finally, we emphasize the role of p25/Cdk5 kinase complex in this pathological process through retinoblastoma protein phosphorylation and derepression of E2F-responsive genes and other actors such as cdc2, cyclins, and MCM proteins.