May 18, 2024
Potential Key to Improved Brain

Neurons Re-entering the Cell Cycle in Neurodegenerative Diseases: A New Insight into Senescence and Alzheimer’s Disease

A recent study published in the open-access journal PLOS Biology reveals that neurons in the brain that reactivate their cell cycle prematurely are more likely to enter senescence, particularly in neurodegenerative diseases such as Alzheimer’s disease. This discovery, made by researchers at the Chinese University of Hong Kong, could provide valuable insights into the neurodegeneration process.

Until recently, it was believed that neurons in the brain were permanently post-mitotic, meaning they had ceased to divide. However, recent research has shown that a small percentage of neurons can re-enter the cell cycle. The fate of these neurons after they re-enter the cell cycle, however, was unknown.

To investigate this question, the researchers analyzed single nucleus RNA sequencing (snRNA-seq) data from over 30,000 neuronal nuclei. By examining the expression levels of cell cycle-related genes, they were able to determine which phase of the cell cycle each nucleus was in at the time of isolation.

Their analysis revealed that a small population of excitatory neurons had indeed re-entered the cell cycle. However, these neurons did not successfully complete the cell cycle and instead entered senescence. This phenomenon was more common in neurons from Alzheimer’s disease patients, with these neurons expressing higher levels of genes associated with senescence and a higher risk of Alzheimer’s disease.

Similarly, neurons in the brains of patients with Parkinson’s disease and Lewy body dementia also showed an increased proportion of re-entering neurons compared to healthy brains.

The significance of this heightened re-entry for neurodegenerative diseases is still unclear, but the analytical approach used in this study may offer deeper insights into neuronal subpopulations within the brain and shed light on disease mechanisms.

Chow, the lead author, noted that the rarity and random localization of these cells in the brain make their molecular profiles and disease-specific heterogeneities difficult to study. However, the applicability of this analytical approach to different diseases and cross-species settings offers new opportunities and insights to supplement traditional histological-based approaches.

The researchers add that their bioinformatics analytical pipeline will provide the field with a new tool to unbiasedly dissect cell cycle re-engaging and senescent neurons and to dissect their heterogeneities in healthy versus disease-affected brains.

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