In Neurodegenerative Disease, More Neurons Return to the Cell Cycle
Researchers have found evidence of cellular senescence in neurons in the aging brain. How do neurons become senescent, given that they are post-mitotic, non-dividing cells? Cellular senescence is state primarily associated with excessive cell division, in which a cell reaches the Hayflick limit, though cells can become senescent in response to damage or toxicity. Here, researchers provide evidence to show that in the aging brain, and particularly in the context of neurodegenerative conditions, ever more neurons re-enter the cell cycle, which inevitably leads to senescence. This is an interesting line of research, adding another argument for the use of senolytic drugs to treat neurodegenerative conditions.
Increasing evidence indicates that terminally differentiated neurons in the brain may recommit to a cell cycle-like process during neuronal aging and under disease conditions. Because of the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear. Through a bioinformatics approach that allows integrated analyses of multiple single-nucleus transcriptome datasets from human brain samples, these rare cell populations were identified and selected for further characterization.
Our analyses indicated that these cell cycle-related events occur predominantly in excitatory neurons and that cellular senescence is likely their immediate terminal fate. Quantitatively, the number of cell cycle re-engaging and senescent neurons decreased during the normal brain aging process, but in the context of late-onset Alzheimer's disease (AD), these cells accumulate instead. Transcriptomic profiling of these cells suggested that disease-specific differences were predominantly tied to the early stage of the senescence process, revealing that these cells presented more proinflammatory, metabolically deregulated, and pathology-associated signatures in disease-affected brains. Similarly, these general features of cell cycle re-engaging neurons were also observed in a subpopulation of dopaminergic neurons identified in the Parkinson's disease (PD)-Lewy body dementia (LBD) model.
An extended analysis conducted in a mouse model of brain aging further validated the ability of this bioinformatics approach to determine the robust relationship between the cell cycle and senescence processes in neurons in this cross-species setting.