A Reevaluation of Tetraploidy in the Alzheimer’s Disease Brain

Alzheimer's disease (AD) is characterized by extensive neuronal death in distinct brain regions, including the frontal cortex and hippocampus, although the specific mechanisms of neuronal degeneration in AD remain a topic of intense scientific pursuit. One model for cell death in AD postulates that abortive cell cycle events in neurons, including tetraploidy, precede neuronal death, and novel therapeutics based on suppressing cell cycle re-entry are being pursued. Using DNA content fluorescence-activated cell sorting combined with fluorescence in situ hybridization and immunostaining, we analyzed neuronal nuclei from postmortem human brain samples from the frontal cortex and hippocampus of nondiseased and AD patients for evidence of tetraploidy. Here, we show that tetraploid nuclei are similarly prevalent in AD and control brains and are exclusively non-neuronal, contrasting with an absence of tetraploid neurons. Our findings demonstrate that neuronal tetraploidy is nonexistent in the AD brain and intimate a reevaluation of neuronal cell cycle re-entry as a therapeutic target for AD.