Posted October 7, 2022

The Central Nervous System (CNS) was historically considered as an immune privileged organ. Key factors contributing to immune privilege were considered to be the blood-brain barrier and the lack of lymphatic drainage of the CNS, which results in a physical disconnect with the immune system. Our lab has shattered the latter assumption by demonstrating the presence of meningeal lymphatics surrounding the brain borders that drain brain-derived molecules into the cervical lymph nodes.”

—Kipnis Lab website

When the lymphatics do not function properly, the impaired drainage that follows is suggested to aggravate AD pathology. A new study reveals that boosting the brain’s meningeal lymphatics and drainage improves the clearance of amyloid beta plaques. The study also showed that improved lymphatic function increased the effectiveness of anti-amyloid immunotherapy.

The results of the study led by CureAlz Research Leadership Group member Jonathan Kipnis, Ph.D., Washington University School of Medicine in St. Louis, suggest that faulty meningeal lymphatics may lead microglia to transition from a homeostatic, “housekeeping” state to a neuroinflammatory, damaging one, leading to loss of neurons. This neuroinflammation is believed by many researchers to be more directly responsible for neuron death than amyloid and tau pathology.  Dr. David Holtzman, M.D., Washington University School of Medicine in St. Louis and member of the CureAlz Research Leadership Group, was also an author of the paper.

The lymphatic system is a network of vessels through which immune cells travel where needed, and fluids, wastes, and toxins are removed from the body’s tissues.  Until recently, scientists believed that the brain did not have lymphatics; exactly how its waste particles exited the brain was unknown.  In 2015, Dr. Kipnis challenged this notion with his discovery of a network of lymphatic vessels in the meninges that drain waste products from the brain.  The meninges are complex layers of cells that encase the brain and spinal cord and form a barrier to the skull and vertebrae. Dr. Kipnis’s research also suggested that normal clearance through the meningeal lymphatics becomes impaired in aging and may contribute to the severity of Alzheimer’s disease pathology.

The Kipnis study suggests that improving drainage of waste and fluid from the brain through the meningeal lymphatic system may improve the efficacy of anti-amyloid antibody immunotherapy drugs.  This class of drug works by tagging aggregated amyloid for degradation by microglia and clearance from the brain. The Kipnis team determined that anti-amyloid immunotherapy reduced the burden of amyloid in the brain in an Alzheimer’s mouse model when the meningeal lymphatics were fully functional than when they were impaired.  Treatment with a compound that restored lymphatic vessels in mice with impaired lymphatic function increased the immunotherapy’s ability to reduce amyloid in the brain.  These findings suggest that anti-amyloid immunotherapy drugs will be most effective when given to patients before their meningeal lymphatics become impaired and that a combination treatment of an anti-amyloid immunotherapy drug and a drug to restore lymphatic function might benefit patients more than either one alone.

Jonathan Kipnis, Ph.D., David Holtzman, M.D., Washington University School of Medicine in St. Louis

Below is a link to the paper published in Nature: