Cell Cycle and DNA Damage Analysis in an Rb/E2F1 Model Related to Alzheimer's Disease

Alzheimer’s disease (AD) causes cognitive dysfunction and memory loss. Adult neurons normally do not divide, but neuronal cell cycle re-entry is a feature of AD that may contribute to neuronal death.  As retinoblastoma protein (Rb) prevents cell cycle by inhibition of E2F proteins, transgenic mice with inactivated Rb and reduced E2F1 were used to examine how cell cycle leads to neurodegeneration. In this study, brain tissues from Rb inactivated mice with E2F1 completely (homozygous) or partially (hemizygous) knocked out were tested for cell cycle progression and DNA damage. If E2F1 is the main factor driving cell cycle, neurons lacking E2F1 would not re-enter cell cycle and die. However, these mice developed unexpected hippocampal cell cycle re-entry and DNA damage with partial cell loss. In hemizygotes, however, there was significant hippocampal neuronal cell cycle re-entry, DNA damage and cell death.  Using E2F1 knockouts, which exhibited slower neurodegeneration, a time course study found that cell cycle induction is followed by DNA damage.  Thus, genetic modification of Rb/E2F1 signaling in neurons uncovered how cell cycle induction precedes DNA damage and apoptosis, and that hippocampal neurons are more susceptible than cortical neurons, suggesting a differential role of Rb/E2F1 signaling in distinct neuronal cell populations.