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Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in
E Barrio-Alonso1, A Hernández-Vivanco2, C C Walton1
1Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute (CSIC), Madrid, Spain.
Scientific Reports
|September 27, 2018
Summary
Alzheimer's disease (AD) neurons re-entering the cell cycle become hyperploid, leading to synaptic failure and impaired function. Maintaining neuronal activity partially rescues synaptic function but not electrical signaling, suggesting a complex role in AD progression.
Area of Science:
- Neuroscience
- Cell Biology
- Alzheimer's Disease Research
Background:
- Cell cycle reentry, neuronal hyperploidy, and synaptic failure are early Alzheimer's disease (AD) hallmarks.
- The functional link between these pathological features remains unclear.
Purpose of the Study:
- To investigate the connection between cell cycle reentry, neuronal hyperploidy, and synaptic dysfunction in Alzheimer's disease.
Main Methods:
- Induced cell cycle reentry in cultured cortical neurons using SV40 large T antigen.
- Assessed neuronal hyperploidy, axon initial segment integrity, PSD-95 puncta density, and synaptic activity.
- Utilized membrane depolarization with high extracellular potassium to evaluate synaptic rescue.
Main Results:
- Cell cycle reentry induced hyperploidy in ~70% of neurons, causing axon loss and reduced PSD-95 puncta.
- Hyperploidy correlated with diminished spike generation and spontaneous synaptic activity.
- Membrane depolarization partially rescued synaptic activity and delayed cell death but did not restore spike generation.
Conclusions:
- Cell cycle reentry and subsequent hyperploidy contribute to synaptic dysfunction in Alzheimer's disease.
- Active neuronal circuits may sustain hyperploid neurons but cannot fully rescue synaptic deficits.
- These findings suggest a role for cell cycle reentry in early cognitive impairment and late-stage neuronal death in AD.
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