Cycle of Decline: Neuron Aging in Alzheimer’s Unraveled

Summary: The neurons of patients with Alzheimer’s disease tend to reenter the cell cycle and progress rapidly toward senescence. Using advanced snRNA-seq techniques, the researchers analyzed more than 30,000 nuclei to track these changes, discovering that these neurons often fail to complete the cell cycle and instead show signs of aging.

This phenomenon, more pronounced in Alzheimer’s, Parkinson’s and Lewy body dementias, could deepen our understanding of neurodegenerative diseases. The study presents a robust bioinformatics tool that provides new insights into the behavior of neurons in diseased or healthy brains.

Highlights:

1. Neurons that reenter the cell cycle in neurodegenerative diseases like Alzheimer’s disease often fail to produce new cells and instead progress toward senescence.
2. The study used snRNA-seq data to analyze the expression of approximately 350 cell cycle-related genes in individual neurons, revealing increased cell cycle reentry in disease-affected brains.
3. This research not only highlights the potential link between cell cycle re-entry and neurodegeneration, but also introduces a new bioinformatics approach to study these processes under different conditions.

Source: PLOS

Post-mitotic neurons in the brain that re-enter the cell cycle quickly succumb to senescence, and this re-entry is more common in Alzheimer’s disease, according to a new study published April 9.^th in the open access journal Biology PLOS by Kim Hai-Man Chow and colleagues at the Chinese University of Hong Kong.

The phenomenon could provide an opportunity to learn more about the process of neurodegeneration, and the technique used to make this discovery is easily applicable to further research on unique populations of brain cells.

Most neurons in the brain are post-mitotic, meaning they have stopped dividing. For many years, it was assumed that this post-mitotic state was permanent. Recent findings have shown that a small proportion of neurons re-enter the cell cycle, but little is known about their fate after that.

To answer this question, the authors turned to publicly available databases of “snRNA-seq” data, in which individual nuclei are isolated and their RNA is sequenced, providing a snapshot of what a cell was doing. at the time of isolation.

The cell cycle proceeds through distinct phases, including growth, DNA synthesis, division-specific growth, and mitosis, and each phase is characterized by a specific set of proteins necessary for its completion. This allowed the authors to use all of the RNAs to tell them in which phase of the cycle a specific nucleus was located.

Their data included information on more than 30,000 nuclei, each of which was assigned a score based on the expression level of a set of about 350 cell cycle-related genes.

They found that small populations of excitatory neurons were indeed reentered into the cell cycle. However, for the most part, these cells failed to continue through the cell cycle to produce daughter neurons.

Instead, cells undergoing reentry also had elevated expression of senescence-associated genes; in fact, the cells had only awakened to enter senescence.

Intriguingly, the authors found that neurons in the brains of Alzheimer’s patients reentered the cell cycle at a higher rate, and that neurons that were reentered the cell cycle and aged showed increased expression of several genes. associated with a higher risk of Alzheimer’s disease. including those that directly contribute to the production of amyloid, the sticky protein that aggregates in the AD brain.

Similarly, the brains of patients with Parkinson’s disease and dementia with Lewy bodies had an increase in the proportion of reentrant neurons compared to healthy brains.

The neurobiological significance of this increased reentry for the diseased brain is not yet clear, but the analytical approach taken here could offer deeper insights into neuronal subpopulations in the brain, as well as shed light on the pathological mechanisms of diseases. neurodegenerative.

“Due to the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear,” Chow said.

“Although experimental validations of these results on relevant human samples will be conducted in the future, the applicability of this analytical approach to different diseases and in cross-species contexts offers new opportunities and perspectives to complement histological approaches to basis in the study of the roles of these elements. cells in brain aging and disease pathogenesis.

The authors add: “This demonstrated bioinformatics analytical pipeline will offer the field a new tool to unbiasedly dissect cell cycle re-engaging and senescent neurons, and to dissect their heterogeneities in healthy and disease-affected brains.

About this Alzheimer’s disease research news

Author: Claire Turner
Source: PLOS
Contact: Claire Turner – PLOS
Picture: Image is credited to Neuroscience News

Original research: Free access.
“Neural cell cycle re-entry events in the aging brain are more frequent in neurodegeneration and lead to cellular senescence” by Kim Hai-Man Chow et al. Biology PLOS

Abstract

Neuronal cell cycle re-entry events in the aging brain are more common in neurodegeneration and lead to cellular senescence

Increasing evidence indicates that terminally differentiated neurons in the brain can reengage in a cell cycle-like process during neuronal aging and in pathological conditions.

Due to the rare existence and random localization of these cells in the brain, their disease-specific molecular profiles and heterogeneities remain unclear.

Using a bioinformatics approach that enables integrated analyzes of multiple mononuclear transcriptome datasets from human brain samples, these rare cell populations were identified and selected for further characterization.

Our analyzes indicated that these cell cycle-related events occur primarily in excitatory neurons and that cellular senescence is likely their immediate terminal fate.

Quantitatively, the number of senescent and cell cycle re-engaging neurons decreased during the normal process of brain aging, but in the context of late-onset Alzheimer’s disease (AD), these cells accumulate instead.

Transcriptomic profiling of these cells suggests that disease-specific differences were primarily related to the early stage of the senescence process, revealing that these cells exhibited more pro-inflammatory, metabolically dysregulated, and pathology-associated signatures in brains affected by disease.

Similarly, these general characteristics of cell cycle re-engaging neurons were also observed in a subpopulation of dopaminergic neurons identified in the model of Parkinson’s disease (PD) and Lewy body dementia (LBD).

An in-depth analysis conducted on a mouse model of brain aging further validated the ability of this bioinformatics approach to determine the robust relationship between cell cycle and senescence processes in neurons in this cross-species context.