Cerebrospinal fluid circulates in the brain. It is created in the choroid plexus and then drains from the brain via a range of pathways. One of the major drainage routes for cerebrospinal fluid is the glymphatic system, discovered and mapped by the research community only comparatively recently. The passage of cerebrospinal fluid from the brain is important as it allows for the removal of metabolic waste. Unfortunately, a reduced drainage of cerebrospinal fluid is a feature of aging, and thought to contribute meaningfully to the development of neurodegenerative conditions. Lost drainage capacity leads to the build up of metabolic waste that would otherwise be removed in a timely fashion. That in turn may contribute to, for example, the increasing overactivation of microglia in the brain and chronic inflammation of brain tissue.
Given the similarities between the glymphatic system and other fluid passage systems in the body, it is possible that existing small molecule drugs may be able to force aged glymphatic vessels into greater drainage capacity, overriding whatever environmental and signaling alterations are leading to tissue dysfunction. In today’s research materials, this is the focus. The researchers better mapped the structure of glymphatic vessels, and found dysfunctional smooth muscle tissue that could act as a target for an existing mode of therapy known to provoke greater smooth muscle contractions. The result was, in mice, at least, a restoration of youthful glymphatic drainage capacity.
Alzheimer’s, Parkinson’s, and other neurological disorders can be seen as “dirty brain” diseases, where the brain struggles to clear out harmful waste. Aging is a key risk factor because, as we grow older, our brain’s ability to remove toxic buildup slows down. However, new research in mice demonstrates that it’s possible to reverse age-related effects and restore the brain’s waste-clearing process.
Once laden with protein waste, cerebrospinal fluid (CSF) in the skull needs to make its way to the lymphatic system and, ultimately, to the kidneys, where it is processed along with the body’s other waste. The new research combines advanced imaging and particle-tracking techniques to describe for the first time in detail the route by way of the cervical lymph vessels in the neck through which half of dirty CSF exits the brain.
Unlike the cardiovascular system, which has one big pump – the heart – fluid in the lymphatic system is instead transported by a network of tiny pumps. These microscopic pumps, called lymphangions, have valves to prevent backflow and are strung together, one after another, to form lymph vessels. The researchers found that as the mice aged, the frequency of contractions decreased, and the valves failed. As a result, the speed of dirty CSF flowing out of the brains of older mice was 63 percent slower compared to younger animals.
The team then set out to see if they could revive the lymphangions and identified a drug called prostaglandin F2α, a hormone-like compound commonly used medically to induce labor and known to aid smooth muscle contraction. The lymphangions are lined with smooth muscle cells, and when the researchers applied the drug to the cervical lymph vessels in older mice, the frequency of contractions and the flow of dirty CSF from the brain both increased, returning to a level of efficiency found in younger mice.
Restoration of cervical lymphatic vessel function in aging rescues cerebrospinal fluid drainage
Cervical lymphatic vessels (cLVs) have been shown to drain solutes and cerebrospinal fluid (CSF) from the brain. However, their hydrodynamical properties have never been evaluated in vivo. Here, we developed two-photon optical imaging with particle tracking in vivo of CSF tracers (2P-OPTIC) in superficial and deep cLVs of mice, characterizing their flow and showing that the major driver is intrinsic pumping by contraction of the lymphatic vessel wall.
Contraction frequency and flow velocity were reduced in aged mice, which coincided with a reduction in smooth muscle actin expression. Slowed flow in aged mice was rescued using topical application of prostaglandin F2α, a prostanoid that increases smooth muscle contractility, which restored lymphatic function in aged mice and enhanced central nervous system clearance. We show that cLVs are important regulators of CSF drainage and that restoring their function is an effective therapy for improving clearance in aging.
