Divide and die: cell cycle events as triggers of nerve cell death

For over a decade, evidence has mounted that nerve cell death in the CNS is often intimately linked to a process of cell division. Mitotic markers appear in neurons at risk for death in a variety of neurodegenerative conditions, in mouse and in humans. Beyond correlation, studies have shown that experimentally driving the cell cycle in a mature neuron leads to cell death rather than cell division, and blocking cell-cycle initiation can prevent many types of neuronal cell death. This unlikely linkage of cell cycle and cell death pathways is little appreciated among neuroscientists. As only one example, bromodeoxyuridine (BrdU) labeling is often uncritically accepted as proof of neurogenesis when it may well be attributable to a cell cycle-related cell death. This review is meant to enhance appreciation for the relevance of this phenomenon to development and neurodegenerative diseases, in particular the neurodegeneration found in Alzheimer’s disease (AD). A brief overview of the participation of mitotic events in human Alzheimer’s disease and its mouse models is presented. Against this background, we consider evidence that links various APP(amyloid precursor protein) binding proteins with the cell cycle in Alzheimer’s disease. We also examine the role played by oxidative stress as a trigger for cell cycle-related neuronal death. Finally, we discuss the biochemical details of the lethal neuronal cell cycle events and present evidence that non-canonical pathways of DNA replication are probably involved.