Rapid initiation of cell cycle reentry processes protects neurons from amyloid-β toxicity

Significance The FUCCI reporter system allows live monitoring of the cell cycle via temporal expression of fluorescence markers of G0/1 or S/G2/M cell cycle phases. We found transient FUCCI reporter activity in naive neurons but not cell division, suggesting that the postmitotic state of neurons is rather a dynamic process of suppressing the cell cycle than a definite G0 state. Exposing neurons to amyloid-β resulted in death of the majority of neurons without cell cycle contribution. A subset of neurons that entered early stages of cell cycle and maintained this state were protected from amyloid-β-induced cell death. Consistently, we found high FUCCI reporter activity in the brains of mice that form amyloid-β through transgenic expression of the amyloid-β precursor protein. Neurons are postmitotic cells. Reactivation of the cell cycle by neurons has been reported in Alzheimer’s disease (AD) brains and models. This gave rise to the hypothesis that reentering the cell cycle renders neurons vulnerable and thus contributes to AD pathogenesis. Here, we use the fluorescent ubiquitination-based cell cycle indicator (FUCCI) technology to monitor the cell cycle in live neurons. We found transient, self-limited cell cycle reentry activity in naive neurons, suggesting that their postmitotic state is a dynamic process. Furthermore, we observed a diverse response to oligomeric amyloid-β (oAβ) challenge; neurons without cell cycle reentry activity would undergo cell death without activating the FUCCI reporter, while neurons undergoing cell cycle reentry activity at the time of the oAβ challenge could maintain and increase FUCCI reporter signal and evade cell death. Accordingly, we observed marked neuronal FUCCI positivity in the brains of human mutant Aβ precursor protein transgenic (APP23) mice together with increased neuronal expression of the endogenous cell cycle control protein geminin in the brains of 3-mo-old APP23 mice and human AD brains. Taken together, our data challenge the current view on cell cycle in neurons and AD, suggesting that pathways active during early cell cycle reentry in neurons protect from Aβ toxicity.