CD49a linked aging of the brain's lymphatic vessels to immune dysregulation

Removing CD49a from the lymphatic vessels in the membranes surrounding the brain improved learning in aged female mice

In a preprint published on August 9, the authors disabled Itga1, the gene encoding CD49a, in lymphatic endothelial cells of the dura mater. In aged female mice, this intervention altered the immune environment around the brain, the state of cortical glial cells, and performance in learning tests.

Lymphatic vessels run along the dura mater. They drain fluid and immune cells from the cerebrospinal fluid into the deep cervical lymph nodes. A 2015 study described this network, and a 2018 study linked greater activity in this network to better learning and memory in aged mice. The new preprint examines which age-related change in the vessel wall may affect the exit of immune cells.

In aged mice, cells in these vessels produce more CD49a, a protein that helps cells adhere to the surrounding collagen. At six weeks of age, the authors induced deletion of the gene encoding this protein. They later compared female mice at 18 and 21 months of age with their littermates.

The authors assessed fluid drainage and immune cell exit separately. They injected a test protein into the cerebrospinal fluid, then tracked the movement of labeled CD4 T-cells, a type of immune cell, into the lymph nodes. Drainage of the test protein did not change. However, in 18-month-old females lacking CD49a, levels of CCL21 increased. Lymphatic vessels use this chemical signal to guide T-cells toward an exit. After 12 hours, more of these cells had reached the deep cervical lymph nodes. In cultured cells, prolonged activation of CD49a reduced the abundance of proteins needed to package and release CCL21.

The immune environment in the membranes surrounding the brain also changed in the same model. In the cerebral cortex, glial cells that support neuronal function were less likely to activate sets of genes associated with aging. Microglia, the brain's immune cells, retained a more highly branched shape. At 21 months of age, the females found the escape box faster in the Barnes maze, a circular platform with holes, and chose a direct route to it more often.