A common protein produced by specialized barrier cells in the brain appears to protect the brain from age-related damage. This protein—MARCKS—helps ependymal cells clear away accumulated molecules and maintain the integrity of the barrier that separates cerebrospinal fluid (CSF) from brain tissue. When MARCKS is absent in these cells, their ability to act as both a barrier and a transport interface for CSF is compromised, accelerating functional decline.
Your brain is cushioned and supported by cerebrospinal fluid (CSF), a clear fluid produced in the brain that distributes nutrients and chemical signals taken from the blood and removes metabolic waste. Like blood, CSF flows through specific channels and compartments. The thin layer of ependymal cells that lines the brain’s ventricles forms both a physical barrier and a regulated transport surface that controls exchange between the CSF and the central nervous system.
Despite their importance, ependymal cells have not been extensively characterized. H. Troy Ghashghaei, associate professor of neurobiology at North Carolina State University, sought to better understand how these cells develop and function. His team investigated what happens when ependymal cells lack the MARCKS protein. “We originally knocked out the MARCKS protein in ependymal cells to see if it played a role in their development, but its absence didn’t appear to affect normal development,” Ghashghaei said. “Instead, we found that ependymal cells without MARCKS appeared to age rapidly, losing some of their barrier and transport functions.”
The researchers observed notable changes when MARCKS was removed. Ependymal cells accumulated higher levels of mucins—mucous molecules typically associated with the respiratory and gastrointestinal tracts—and lipids, or fats. The presence and potential role of mucins in the brain had not been well characterized before this work.
Elevated mucins and lipid accumulation correlated with increased oxidative stress inside ependymal cells. This oxidative burden weakened the cells’ barrier function, diminishing their ability to regulate the flow and composition of CSF. Surprisingly, loss of barrier function in these cells produced signs of accelerated aging beyond the ependymal layer, affecting surrounding brain tissue. The findings suggest that maintaining MARCKS-dependent processes in ependymal cells supports brain homeostasis and may help delay or prevent age-associated decline in brain function.
“It seems that MARCKS is critical for the trafficking and clearance of some proteins through these ependymal cells,” Ghashghaei explained. The team found that older ependymal cells exhibit similar increases in oxidative stress and reduced barrier performance. Whether MARCKS loss or the natural aging process impairs ependymal function, the consequence may be the initiation or exacerbation of neurological conditions and cognitive decline.
The idea that a thin epithelial layer lining the ventricles can influence brain aging offers a new perspective on age-associated brain disorders and therapeutic strategies. Preserving MARCKS-dependent clearance and lipid-handling mechanisms in ependymal cells may be a promising avenue to maintain forebrain homeostasis with age.
Funding: This work was supported by grants from the National Institutes of Health and the American Federation for Aging Research.
Source: Tracey Peake – North Carolina State University
Image Credit: Image adapted from the North Carolina State University article
Original Research: Full open access research: “MARCKS-dependent mucin clearance and lipid metabolism in ependymal cells are required for maintenance of forebrain homeostasis during aging” by Nagendran Muthusamy, Laura J. Sommerville, Adam J. Moeser, Deborah J. Stumpo, Philip Sannes, Kenneth Adler, Perry J. Blackshear, Jill M. Weimer and H. Troy Ghashghaei in Aging Cell. Published online May 25 2015. doi:10.1111/acel.12354
Abstract
MARCKS-dependent mucin clearance and lipid metabolism in ependymal cells are required for maintenance of forebrain homeostasis during aging
Ependymal cells (ECs) form a selective barrier responsible for directional movement of fluids and molecules between the cerebrospinal fluid and the central nervous system. This study shows that key metabolic and barrier functions of ECs decline significantly during aging in mice. Sustaining these functions depends in part on the myristoylated alanine-rich C-kinase substrate (MARCKS). Both expression and subcellular localization of MARCKS in ECs change markedly with age. Conditional deletion of MARCKS in ECs causes intracellular accumulation of mucins, increased oxidative stress, and buildup of lipid droplets. These changes accompany early disruption of ependymal barrier function and are associated with increased activation of astrocytes, microglia, and infiltrating macrophages in the forebrain interstitium of young mutant mice. Similar cellular alterations are observed during normal aging in ECs and forebrain tissue. Together, the data introduce a new paradigm in which EC dysfunction may contribute to initiation and progression of age-related neurological conditions.
“MARCKS-dependent mucin clearance and lipid metabolism in ependymal cells are required for maintenance of forebrain homeostasis during aging” by Nagendran Muthusamy et al., Aging Cell. Published online May 25 2015. doi:10.1111/acel.12354