Differentiated neurons can undergo cell cycle re-entry during pathological conditions, but it remains largely accepted that M-phase is prohibited in these cells. Here we show that primary neurons at post-synaptogenesis stages of development can enter M-phase. We induced cell cycle re-entry by overexpressing a truncated Cyclin E isoform fused to Cdk2. Cyclin E/Cdk2 expression elicits canonical cell cycle checkpoints, which arrest cell cycle progression and trigger apoptosis. As in mitotic cells, checkpoint abrogation enables cell cycle progression through S and G2-phases into M-phase. Although most neurons enter M-phase, only a small subset undergo cell division. Alternatively, neurons can exit M-phase without cell division and recover the axon initial segment, a structural determinant of neuronal viability. We conclude that neurons and mitotic cells share S, G2 and M-phase regulation.

When subjected to stress, terminally differentiated neurons are susceptible to reactivate the cell cycle and become hyperploid. This process is well documented in Alzheimer's disease (AD), where it may participate in the etiology of the disease. However, despite its potential importance, the effects of neuronal hyperploidy (NH) on brain function and its relationship with AD remains obscure. An important step forward in our understanding of the pathological effect of NH has been the development of transgenic mice with neuronal expression of oncogenes as model systems of AD. The analysis of these mice has demonstrated that forced cell cycle reentry in neurons results in most hallmarks of AD, including neurofibrillary tangles, Aβ peptide deposits, gliosis, cognitive loss, and neuronal death. Nevertheless, in contrast to the pathological situation, where a relatively small proportion of neurons become hyperploid, neuronal cell cycle reentry in these mice is generalized. We have recently developed an in vitro system in which cell cycle is induced in a reduced proportion of differentiated neurons, mimicking the in vivo situation. This manipulation reveals that NH correlates with synaptic dysfunction and morphological changes in the affected neurons, and that membrane depolarization facilitates the survival of hyperploid neurons. This suggests that the integration of synaptically silent, hyperploid neurons in electrically active neural networks allows their survival while perturbing the normal functioning of the network itself, a hypothesis that we have tested in silico. In this perspective, we will discuss on these aspects trying to convince the reader that NH represents a relevant process in AD.