Neuronal cell cycle reentry events in the aging brain are more prevalent in neurodegeneration and lead to cellular senescence

• Published in: PLoS biology Vol. 22; no. 4; p. e3002559
• Main Authors: Wu, Deng, Sun, Jacquelyne Ka-Li, Chow, Kim Hei-Man
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.04.2024; Public Library of Science (PLoS)
• Subjects: Aged; Aging; Aging - genetics; Aging - physiology; Algorithms; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Bioinformatics; Biology and Life Sciences; Brain; Brain - metabolism; Brain - pathology; Brain research; Cell cycle; Cell Cycle - genetics; Cellular Senescence - genetics; Computer and Information Sciences; Cyclin-dependent kinases; Degeneration; Dementia disorders; Deregulation; Dopamine receptors; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Gene expression; Gene Expression Profiling; Health aspects; Humans; Inflammation; Kinases; Lewy bodies; Localization; Male; Medicine and Health Sciences; Metadata; Mice; Mice, Inbred C57BL; Movement disorders; Nervous system; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurons; Neurons - metabolism; Neurons - pathology; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Scholarships & fellowships; Senescence; Short Reports; Transcriptome - genetics; Transcriptomes; Transcriptomics; China
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3002559

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.