The involvement of cell cycle events in the pathogenesis of Alzheimer’s disease Karl Herrup* Most neurons undergo their last cell division within the first 1 to 2 % of the lifespan of an organism. This has been interpreted to mean that adult neurons are permanently postmitotic, but Alzheimer’s disease (AD) is an example of a late-onset neurodegenerative disease that challenges this concept. In AD, neurons in populations at risk for death reactivate their cell cycle and replicate their genome – but rather than complete the cycle with mitosis and cytokinesis, the neurons die. While opening new perspectives on the etiology of AD dementia, the simple linear model suggested by this description gains in complexity with the maturation of the adult brain. This complexity makes the full understanding of the relationship between cell division and cell death more difficult to achieve. The quest for understanding is worthwhile, however, as fresh avenues for therapeutic intervention are the prizes for success. For most central nervous system neurons, emigration from the ventricular zone marks their entrance into a state from which they will never normally re-enter a cell cycle. The prohibition against cell division in this new state of existence is sufficiently strong that if a neuron does try to divide then it will die. The molecular mechanisms that link cell cycle to cell death in this situation are not fully understood, but the relationship is completely straightforward in young postmitotic neurons. As documented in several laboratories, if a neuron is forced to divide by expression of an oncogene, it will re-enter a cycle and die. If any of several cell cycle suppressor functions are lost, the neuron will re-enter a cycle and die. If a cultured neuron is exposed to oxidative stress, DNA damaging agents or certai
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