P3‐317: Failure in the control of cell cycle causes neurodegeneration

Re-activation of cell cycle in neurons has emerged as a potential pathogenic mechanism of neuronal dysfunction/death in many neurodegenerative diseases such as Alzheimer disease (AD). However, the link between cell cycle re-entry and neurodegeneration in vivo has not been fully elucidated primarily because of the lack of an animal model to determine the effects of cell cycle re-entry in adult post-mitotic neurons. The retinoblastoma protein (Rb) stalls progress through cell cycle to S phase by binding with E2F family proteins. In proliferating cells, Rb is hyperphosphorylated and E2F is thereby released to allow cell cycle progression. Interestingly, hyperphosphorylated Rb is strongly increased in the vulnerable neurons in AD suggesting that a loss of cell cycle check point control causes cell cycle re-entry in AD. Objective(s): We sought to investigate the effect of failure in neuronal cell cycle control and its implications in the pathogenesis of AD. We developed a novel transgenic mouse model which can be induced to specifically drive forebrain neurons into the cell cycle through functional ablation of Rb to study the functional consequences of a failure in neuronal cell cycle control. Since Rb is ablated after embryonic developmental stages, our mouse model, unlike previously established animal models, truly represents the effect of loss of cell cycle control in post-mitotic neurons. Markers of cell cycle and neurodgeneration were examined and their relationships were further analyzed. In our animal model, the loss of Rb in post-mitotic neurons, which mimics the effect of hyperphosphorylation, drives fully developed neurons to re-enter the cell cycle and triggers progressive neurodegeneration. Since Rb is available during embryogenesis, no detrimental effect during development was observed. The long-term effects of cell cycle re-entry on the development of AD related pathology such as amyloid-β and tau phosphorylation will be discussed. Our findings provide compelling evidence that disregulation of cell cycle re-entry plays a causative role in neurodegeneration in vivo and, coupled with previous reports, leads us to the hypothesis that neurodegeneration in AD, like cellular proliferation in cancer, is a disease of inappropriate cell cycle control.