Unveiling the Complex Relationship Between Neurons and Microglia: A New Study on Protein Degradation and Aging
Aging neurons face a unique challenge: how to dispose of their waste. As we age, our cells struggle to keep up with the natural process of clearing out old and damaged proteins, which can lead to a buildup of toxic waste. But here's where it gets controversial: a new study suggests that neurons may outsource this task to microglia, the brain's immune cells. This discovery raises important questions about the role of microglia in aging and neurodegenerative diseases.
The study, published in Nature, found that synaptic proteins in aged mice degrade more slowly than in younger mice. This slower turnover may be due to microglia taking on the role of waste disposal for neurons. However, this process could become toxic if the accumulation of proteins isn't properly managed. The findings highlight the complex relationship between neurons and microglia, and the potential impact of protein buildup on brain health.
Neurons face unique challenges to protein turnover, says Ian Guldner, a postdoctoral fellow at Stanford University. Unlike other cells, neurons can't distribute old proteins among daughter cells, and their long lifespan means that proteins must navigate the axon to reach the cell body. This journey can be as long as 1 meter! To study protein degradation in neurons, Guldner and his team engineered mice to express a modified enzyme in excitatory neurons, allowing them to track protein turnover over two weeks.
The study revealed that the average half-life of proteins in excitatory neurons doubles between young and aged mice, suggesting that synapses may be particularly vulnerable to declining protein turnover. Furthermore, many of these destruction-resistant proteins are involved in synaptic function, which could explain why synapses are often affected in aging and neurodegenerative diseases.
Protein aggregation also rises with age, and these clumps can clog the degradation machinery. To identify all the proteins in neuronal aggregates, Guldner and his team isolated tagged protein aggregates. They found that about half of the 1,726 proteins in the neuronal 'aggregome' show age-related increases in longevity, including many synaptic proteins. Interestingly, some of these proteins were also found in microglia, especially in aged mice.
Neurons may be outsourcing their waste disposal to microglia, says Thibault Mayor, a professor of biochemistry and molecular biology at the University of British Columbia. This finding raises important questions about the role of microglia in aging and neurodegenerative diseases. However, it's unclear whether neurons create more waste with age or if microglia are worse at dealing with it. More research is needed to understand the complex relationship between neurons and microglia and the impact of protein buildup on brain health.
What starts as a protective mechanism could backfire, says Guldner. As microglia age, they may begin to hoard dysfunctional proteins, leading to a buildup of toxic waste. This process could contribute to the spreading of protein aggregates and age-related synapse loss, which are hallmarks of neurodegenerative diseases. Further research is needed to understand the complex relationship between neurons and microglia and the impact of protein buildup on brain health.
The next steps in this research could involve investigating whether the changes observed in aged mice are accelerated in Alzheimer's disease models, says Guldner. The team is also interested in how protein turnover varies across different brain cell types and tissues, including the cerebellum and white matter. Microglia in these regions are particularly sensitive to aging, according to previous studies from the lab. These experiments would require more sensitive equipment or pooling animals to reach detectable protein levels, which are ambitious efforts.
