In diseases such as Alzheimer’s and Parkinson’s, harmful proteins accumulate in nerve cells and cause them to die. A study has now uncovered a previously unknown protective mechanism: According to it, immune cells in the brain, the microglia, form tiny tubes to the nerve cells through which they transport harmful proteins away and deliver useful substances. The findings provide new approaches for the prevention and treatment of neurodegenerative diseases.
Many neurodegenerative diseases arise when certain proteins in the nerve cells change pathologically and accumulate. In Alzheimer’s, for example, this is the tau protein, which normally ensures the stability and nutrient supply of the cell; in Parkinson’s, it is the protein alpha-synuclein, which regulates, among other things, the release of dopamine. If too many defective proteins accumulate within a nerve cell, the cell dies – the beginning of neuronal degeneration.
Direct help through tunnels
A team led by Hannah Scheiblich from the Max Planck Institute for Biology of Ageing in Cologne has now discovered a protective mechanism with which certain immune cells in the brain, the microglia, protect nerve cells from this fate. “Microglia play a crucial role as the brain’s control and cleanup crew,” the researchers explain. “They actively remove abnormal protein aggregates. However, it was previously assumed that microglia usually only encounter these pathological proteins after neurons have died.”
Scheiblich and her team have now discovered a way for microglia to intervene before it is too late: “We have shown that microglia form tiny tunnel nanotubes in both healthy brains and in pathological changes, with which they establish connections to neurons in order to quickly exchange organelles, vesicles and proteins,” the team reports. “The microglia use these tubes to free neurons of toxic protein aggregates and restore neuronal health.” The researchers demonstrated that such tubes form in both cell cultures and in living mice.
Waste channels and supply tunnels at the same time
Due to limitations in imaging, Scheiblich and her colleagues were unable to directly observe the transport of proteins through these tubes. However, they showed that in systems with functioning tubes, harmful alpha-synuclein aggregates from living nerve cells reached the mitochondria. “In addition, we found that the microglia share their healthy mitochondria – the power plants of the cells – with the stressed neurons, thereby reducing oxidative stress and normalizing gene expression,” the researchers explain. The nanotubes are therefore not only a way to dispose of waste, but also function in the other direction as a supply tunnel to strengthen the stressed nerve cells.
“Our results open up the potential to directly intervene in the health of neurons by improving the natural functions of microglia,” says Scheiblich’s colleague Frederik Eikens. As the research team discovered, certain mutations in the microglia can cause the formation of the tubes to be impaired – associated with an increased risk of neurodegenerative diseases. “Our next steps will focus on understanding how these tubes are formed and finding ways to stimulate this process in diseases,” says Scheiblich’s colleague Lena Wischhof.
Source: Hannah Scheiblich (Max Planck Institute for Biology of Ageing, Cologne) et al., Neuron, doi: 10.1016/j.neuron.2024.06.029