A recent study reveals that as we age, the brain’s “garbage disposal” system becomes less effective. This is particularly true for long-lived neurons, which begin to transfer clumpy, old proteins onto other cells in the brain.
These proteins play a key role in signaling between brain cells at synapses—those tiny gaps where neurons communicate. However, in older adults, certain changes prevent these proteins from breaking down effectively, leading to blockages at the synapses.
Support cells, known as microglia, try to help by trimming away the clogged synapses to keep the neurons active. Still, researchers suggest this might inadvertently hinder communication between brain cells.
The findings provide insight into our understanding of neurodegenerative diseases and might open up new possibilities for treatment.
Loss and dysfunction of synapses have been tied to cognitive decline in aging, and symptoms have been seen in Alzheimer’s and other neurodegenerative conditions. However, the process that results in these synaptic issues is likely quite complicated.
“We weren’t specifically looking at synapses but rather at what happens to neuron health and function as we get older,” explains Ian Guldner, a neuroscientist at Stanford University. “Interestingly, we discovered that synaptic proteins are particularly susceptible to slow breakdown and clumping.”
The brain, with its approximately 86 billion neurons, is a complex network, where each cell can connect with up to 10,000 others. This creates more than a quadrillion synapses, maintained by these synaptic proteins, which support neuron growth and regulate the release of neurotransmitters—the chemicals that relay signals.
Initially, the researchers wanted to examine how protein recycling adapts with age in live animals. They tagged and monitored thousands of proteins in mice of different ages—young, middle-aged, and older.
Using a novel biological tag incorporated into proteins during their formation, they studied how long proteins persisted before being recycled. Their experiments showed that brain cells of older mice (about 24 months) had a much harder time recycling proteins compared to younger ones (around 4 months).
Specifically, neurons in older mice took nearly twice as long to recycle their proteins, leading to a greater buildup of these proteins over time. This slowdown became noticeable after middle-age.
Additionally, the study found that neurons transfer clumpy proteins to microglia, which act as both the immune system’s first line of defense and the brain’s waste disposal. Aside from cleaning up these waste proteins, microglia also prune damaged synapses to maintain neural health.
“If microglia are overwhelmed by the influx of damaged proteins, it could lead to their dysfunction, negatively impacting overall brain health,” Guldner notes.
The precise reasons why synaptic proteins are more prone to becoming tangled remain unclear, but the findings suggest a link between synaptic loss and microglial dysfunction—both of which could contribute to neurodegenerative diseases in older individuals.
Interestingly, some proteins taken up by microglia are already associated with conditions like Alzheimer’s and Parkinson’s disease. However, many previously unlinked proteins were also discovered.
“The real breakthrough here is our technical advancement, allowing us to observe protein degradation and aggregation specifically in neuronal cells,” commented biochemist F. Ulrich Hartl, director at the Max Planck Institute of Biochemistry, who was not part of the study.
“If we can utilize this method to study neuron-derived proteins in the blood during aging and illness,” Guldner adds, “we might identify new biomarkers for brain health.”
This research has been published in Nature.
