fMRI of the brain reveals distinct patterns in aging dementia

Much of the lab’s prevention research focuses on dementia that is caused by a change in gene expression of brain cells. Yet cells with altered genes become more and more vulnerable to cognitive decline and eventually become disabled. In a new study, a team led by Yale-New Haven Hospital researchers found unequivocally that a key brain stem-cell regulator is regulated by two subtypes of dendritic cells.

The team’s finding, Published online in Cell Reports, sheds light on the fact that certain dendritic cells reserve for neural activity that is needed for sustaining cognitive function. The finding also suggests that stimulation of specific proteins called dendritic repair factors may be a good drug target for treating cognitive dysfunction linked to changing genes in the brain.

The work began when the team discovered that small electrical fluctuations within brain stem-cells called astrocytes, which cover the forebrain and spinal cord, were directly regulated by gene expression changes in approximately 35d-year-old controls. Gene expression motifs (RNAs) that replaced cellular elements were associated with their behavior, suggesting that gene regulation affects the ability of microglia-forming cells to perform certain important functions or stores memory. The work further indicated that the regulation of cell population-level activity by RNA does not occur in normal aging.

“We show that changes in these molecular regulators themselves are mediated by changes in gene expression of microglia that are exclusively expressed in astrocytes, ” said senior author Mark Svendsen, assistant professor of genetics and of neurobiology at Yale-New Haven Hospital near the campus of the Department of Neurology, Yale-Lancet. “They are not expressed in microglia of similar maturity of the subjects we studied. “

“We showed that measures of neuronal activity are specifically regulated by regulation of microglia expression of RNA by dendritic primordia in the astrocytes, ” he continued. “This finding establishes a novel relation between RNA trafficking and cell behavior. “

The findings underscore the importance of DNA damage-inducing DNA elements and gene expression in the brain as fundamental causes of cognitive decline. Structural changes, modification and change-over of RNA expression in response to DNA damage have greater importance than the actual sequence of DNA mutations in most cells. In this study, microglia and their regulatory mechanisms were shown to regulate changes in RNA expression by dendritic primordia in the astrocytes.

“We clearly show that dendritic primordia ubiquitinate RNA regulation regulates microglial gene expression, ” said the co-lead author of the study, Dipak Panigrahy, assistant professor in the Department of Biomedical Engineering in the Yale School of Medicine.

Previous studies on RNA trafficking, specifically RNA metabolism, were unsuccessful at assessing the role of microglia-specific molecular regulators, he added.