Finding the stimulants of disease in the aging brain 

Research on the importance of ependymal cells — cells that move fluids between the cerebrospinal fluid and the central nervous system — could introduce a new model for the potential role of these cells in the onset of various diseases in the aging brain.

Troy Ghashghaei, the lead researcher on the project, and his colleagues produced findings that suggest a protein in ependymal cells, called myristoylated alanine-rich protein kinase C substrate (MARCKS), may protect the brain from aging.

The physiological system the research team is interested in deals with cerebrospinal fluid and how it works within the brain, as well as how the fluid interacts with blood and the lymphatic system.

“We were studying how [the ependymal cells] develop during embryonic development, and it turns out that they don’t develop during embryonic development,” Ghashghaei said.  “Mostly when animals are born, and it’s probably a similar pattern in humans, they develop in late gestation.”

The team has been studying the cells for more than seven years and has since developed a way to study them functioning in the mature brain.

The researchers studied the cells’ effect on genes by knocking out the gene, making it inoperative to the organism. By using this genetic technique, researchers found that ependymal cells produce a protein called mucin, an important component of mucus that protects cells by forming a layer of film around them.

“We know that these [mucin] are present in the lining of the gut and the lung, but nobody knew that they were also present in the brain,” Ghashghaei said.

The findings from the gene knockout suggested the MARCKS protein helps prevent aging in the ependymal cells that produce mucin and protect other cells. In turn, the way that the ependymal cells are affected by the knockout seemed to produce an effect on the aging of the brain.

“What we found was that the ependymal cells aged a lot faster when we did that,” Ghashghaei said. “When they aged faster, they couldn’t redistribute mucin properly.”

Neurodegenerative diseases have been widely studied by scientists, but the causes and stimulation of many of these diseases are still unknown, so the research on MARCKS and the role of ependymal cells in the aging of the brain could potentially help scientists draw a conclusion about human aging.

“We understand a lot about what happens when a disease, like Parkinson’s or Alzheimer’s, is present,” Ghashghaei said. “We know what the pathologies are, we know what all the biochemical pathways are, but we don’t know what stimulates it.”

However, he said the research suggests infection is an important part of this process.

“In neurodegenerative diseases, these cells in this system is probably the gateway to how you get infections and to immune cells entering the brain,” Ghashghaei said.

Due to the complexity of the research, Ghashghaei said the lab work for the project spanned multiple disciplines, as the research was collaborative in nature.

“It’s a very interdisciplinary approach,” Ghashghaei said. “Basically, it involves almost all aspects of science. We do a lot of it ourselves, but we do collaborate with experts who are good at other things that we’re not good at.”

Some of the collaborations included Ken Adler, an expert in mucin physiology and MARCKS and a researcher who studies how certain cells form barriers between tissues and fluid.

 “We go all the way from microbiology and genetics to physiological analysis,” Ghashghaei said. “We collaborate with a number of labs. Most of those collaborations have to do with getting genetic mice or exchange the mice that we generate with each other.”

The mice used were generated in a colony close to the lab where this research was done.

“We have transgenic mice, so you can use specific genetic models by either inserting genes or deleting specific genes,” said Nagendran Muthusamy, a postdoctoral fellow working in the lab. “We used some genetic deletions so we can target specific cell types also in the brain and then delete the gene of interest.”

The results of this research could improve understanding and treatment of aging in the human brain.

“One of the areas I can think about is in aging because this paper is totally about what happens during aging and what this protein MARCKS is necessary for for normal aging,” Muthusamy said. “Even in young mice, we see patterns and specific structures that are only seen in aging mice that are seen in young mice as well. So I think for better normal, like normal aging in people, this will be a fantastic model.” 

In the beginnings of the research, Ghashghaei and his team weren’t sure what the ependymal cells did, so finding out about brain physiology and aging in the mature brain and how it ages was unexpected.

“That’s what keeps me excited — you always run into unexpected things,” Ghashghaei said.