Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in differentiated cortical neurons
| Autor: | Christopher C. Walton, José María Frade, Estíbaliz Barrio-Alonso, Gertrudis Perea, A. Hernández-Vivanco |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Consejo Superior de Investigaciones Científicas (España) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Programmed cell death SV40 large T antigen Cellular differentiation lcsh:Medicine Biology Polyploidy 03 medical and health sciences Mice 0302 clinical medicine Animals lcsh:Science Neurons Multidisciplinary Cell Death lcsh:R Cell Cycle Brain Depolarization Cell Differentiation Reentry Cell cycle Axon initial segment Oxidative Stress 030104 developmental biology nervous system Synapses lcsh:Q Calcium Female Extracellular Space Neuroscience 030217 neurology & neurosurgery Hyperploidy |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-14 (2018) Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Cell cycle reentry followed by neuronal hyperploidy and synaptic failure are two early hallmarks of Alzheimer’s disease (AD), however their functional connection remains unexplored. To address this question, we induced cell cycle reentry in cultured cortical neurons by expressing SV40 large T antigen. Cell cycle reentry was followed by hyperploidy in ~70% of cortical neurons, and led to progressive axon initial segment loss and reduced density of dendritic PSD-95 puncta, which correlated with diminished spike generation and reduced spontaneous synaptic activity. This manipulation also resulted in delayed cell death, as previously observed in AD-affected hyperploid neurons. Membrane depolarization by high extracellular potassium maintained PSD-95 puncta density and partially rescued both spontaneous synaptic activity and cell death, while spike generation remained blocked. This suggests that AD-associated hyperploid neurons can be sustained in vivo if integrated in active neuronal circuits whilst promoting synaptic dysfunction. Thus, cell cycle reentry might contribute to cognitive impairment in early stages of AD and neuronal death susceptibility at late stages. This work was supported by Ministerio de Economía y Competitividad Grants SAF2015-68488-R (J.M.F.) and BFU2013-47265-R and BFU2016-75107-P (G.P.), and Intramural Grant 201620I017 (G.P.). |
| Databáze: | OpenAIRE |
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