A number of research groups are building convincing evidence to show that reduced drainage of cerebrospinal fluid is an important contributing factor in the development of neurodegenerative diseases. A sizable fraction of these conditions are characterized by the aggregation of forms of altered or misfolded proteins, such as amyloid-β, tau, and α-synuclein. They precipitate to form solid deposits surrounded by a complex halo of biochemistry that harms and eventually kills brain cells. From what is known of amyloid-β, levels are quite dynamic, which all along has suggested that rising amounts in older brains are the result of a growing imbalance between processes of creation and clearance, rather than a slow accumulation over time.
For amyloid-β this informs a range of thinking about the condition, such as viral theories that see amyloid formation as an innate immune response run wild in patients with persistent infection. Or theories involving dysfunction of filtration of cerebrospinal fluid in the choroid plexus, or age-related dysfunction of microglia and other cells responsible for clearing up unwanted metabolic waste such as protein aggregates. Theories focused on the more mechanical aspects of fluid clearance are more recent, and in many ways easier to work with and test. Normally cerebrospinal fluid leaves the central nervous system through a variety of paths, and from what is known today, it appears that all of those paths atrophy with age. Less drainage means less of a chance for protein aggregates to exit the brain to be degraded elsewhere in the body.
Leucadia Therapeutics is somewhat ahead of other development groups in the maturity of their work, and is initially focused on the drainage pathways passing through the cribriform plate. Comparatively simple means of restoring fluid flow in that part of our physiology have the potential to be revolutionary in the treatment of neurodegeneration conditions, a way to simultaneously reduce levels of all pathological protein aggregates and other molecular waste in the brain. Most current attempts at development of treatments focus on just one type, and that may not be enough. Other groups are investigating other pathways of drainage, such as the recently discovered network of lymphatic vessels in the brain. Judging from the publicity materials and paper here, researchers are starting to make real progress on this front. To the degree that any given portion of the fluid flow network in the brain is a part of the larger problem, significant benefits might be achieved via means of restoration.
It turns out that the lymphatic vessels long thought not to exist in the brain are in fact essential to the brain's ability to cleanse itself. New work gives us the most complete picture yet of the role of these vessels - and their tremendous importance for brain function and healthy aging. Researchers were able to use a compound to improve the flow of waste from the brain to the lymph nodes in the neck of aged mice. The vessels became larger and drained better, and that had a direct effect on the mice's ability to learn and remember.
The researchers determined that obstructing the vessels in mice worsens the accumulation of harmful amyloid plaques in the brain that are associated with Alzheimer's. This may help explain the buildup of such plaques in people, the cause of which is not well understood. "In human Alzheimer's disease, 98 percent of cases are not driven by known genetic differences, so it's really a matter of what is affected by aging that gives rise to this disease. As we did in mice, it will be interesting to try and figure out what specific changes are happening in the old brain lymphatics in humans so we can develop specific approaches to treat age-related sickness."
Impairing the vessels in mice had a fascinating consequence: "What was really interesting is that with the worsening pathology, it actually looks very similar to what we see in human samples in terms of all this aggregation of amyloid protein in the brain and meninges. By impairing lymphatic function, we made the mouse model more similar to human pathology." The researchers now will work to develop a drug to improve the performance of the lymphatic vessels in people.
Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic vasculature and waste products are removed partly through a paravascular route. Rediscovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS. Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice.
Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer's disease promotes amyloid-β deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-β accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer's disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.