For the first time, researchers have confirmed the existence of a system that helps to clear waste from the brain in mammals other than rodents.
Results of the research were shared in a preprint called, “Glymphatic function in the gyrencephalic brain,” in BioRxiv. (Preprints are scientific studies that have not yet undergone peer review, which is when experts review the data and conclusions to spot potential flaws or problems.)
Living cells produce waste material, and cells in the brain are no exception. Since many cellular waste products can be toxic if too much accumulates, that waste needs to be removed somehow.
Previous research has shown that rodents (mice and rats) have a system to remove waste from the brain, which has been dubbed the glymphatic system. Conceptually, this is a system in which cerebrospinal fluid flows within a region known as perivascular space (parallel to blood vessels) in the brain, through brain tissue, and then out, basically washing away cellular waste. (Cerebrospinal fluid is the liquid that surrounds the brain and spinal cord.)
Some magnetic resonance imaging (MRI) data from humans have suggested that brain fluid in people is moved by a similar system. However, this idea has been controversial because the type of imaging experiments that are needed to map out the glymphatic system in detail are so invasive that suitable experiments in human subjects haven’t been feasible.
Since studies had been able to identify the system only in rodents, it wasn’t clear whether the glymphatic system was present in larger mammals, too.
To this end, researchers from Lund University in Sweden used detailed imaging experiments to examine the flow of fluid in the brains of pigs. The anatomy of pigs is quite similar to that of humans. Pig and human brains are quite similar. Not only are the brains typically about the same size, but they both have complex folds, whereas rodent brains are comparatively smooth.
“The pig is therefore a suitable intermediate species between mice and humans for the field of glymphatics and pushes the frontiers of our understanding of the glymphatic system and translating this understanding to humans,” the researchers wrote.
The researchers used a combination of techniques to precisely model how fluid moved through the pig brains.
“We made tissue blocks transparent by using ‘optical clearing’ and then imaged them with a ‘light sheet’ microscope, which allowed us to create 3-D-movies. This provided us with an overview of the architecture of the brain’s cleaning system with details that have never been seen before in a large mammal,” study co-author Iben Lundgaard, PhD, said in a press release. Lundgaard is a neuroscientist and associate senior lecturer at Lund University.
The researchers’ experiments confirmed the existence of the glymphatic system in the pigs’ brains.
“Up until now, it was merely an assumption that this cleaning system exists in brains of larger mammals. Now we now know for certain that it exists,” Lundgaard said.
Not only was the glymphatic system present in pigs, it was more developed. About four times more fluid was able to move through pig brains, compared to what has been observed in rodent brains. This difference was linked with the presence of folds in the pig brain.
“We discovered that the cleaning fluid’s entrance to the brain is concentrated along the folds of the brain, which suggests that these folds act as highways for the cleaning system. We also discovered that the cleaning system is much more active in the folded pig brain, which has folds like the human brain, than in the smooth mouse brain,” said study co-author Nicholas Bèchet, a PhD student.
Neurodegenerative diseases are often characterized by the presence of abnormal protein aggregates (clumps) in the brain. For example, Parkinson’s is characterized by aggregates of the protein alpha-synuclein. Experiments in rodent models have indicated that the glymphatic system can aid in the clearance of these protein aggregates.
“These findings are encouraging in terms of potentially utilizing glymphatic function as a therapeutic target against neurodegeneration,” the researchers wrote, noting that more studies in large animals like pigs will be needed before the findings can be translated into people.
“We believe that by enhancing the function of this cleaning system we will be able to slow down or prevent Alzheimer’s disease. This can potentially also be applied to other diseases that are caused by toxic accumulation of the brain’s own waste products, such as Parkinson’s disease,” Lundgaard said.
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