Neurodegenerative Phenotypes Induced by MYC‐Driven Neuronal Cell Cycle Re‐entry: Relevance to Alzheimer Disease

Aberrant cell cycle activation in neurons has emerged as a potential pathogenic mechanism of neuronal dysfunction/death in many neurodegenerative diseases such as Alzheimer disease (AD). However, the exact role of cell cycle re‐entry in disease pathogenesis is unclear, primarily because of the absence of research models to study the effects of cell cycle re‐entry in mature neurons in vivo. To address this issue, we recently developed a new transgenic mouse model which can be induced to specifically re‐drive forebrain neurons into the cell cycle (CaMKII‐MYC). Analysis of these animals shows that driving neurons into the cell cycle leads to many phenotypic changes characteristic of AD including: 1) ectopic expression of cell cycle proteins; 2) hyperphosphorylation of tau; 3) accumulation of intraneuronal amyloid‐beta; 4) a “neurodegenerative” (TUNEL) phenotype; 5) astrogliois; and 6) major cognitive deficits (Y‐maze and Morris Water Maze). Our findings provide compelling evidence that dysregulation of cell cycle re‐entry plays a causative role in neurodegeneration in vivo.