Lymphatic drainage of the brain. Is there a “glymphatic” system?
In most tissues of the body, interstitial fluid (ISF), soluble metabolites and inflammatory cells drain to regional lymph nodes along well-characterised lymphatic vessels. The brain has no conventional lymphatics so: How does the brain connect with the immune system? There are two extracellular fluids associated with the central nervous system (CNS): 1) cerebrospinal fluid (CSF) in the ventricles and subarachnoid spaces and 2) interstitial fluid (ISF) between the cells of the brain and spinal cord.
CSF drains to regional lymph nodes along lymphatic vessels in the nasal mucosa, via the cribriform plate, and along lymphatics associated with nerve roots and the dura mater. Lymphatic drainage pathways for CSF allows traffic of antigen presenting cells, so the leptomeningeal spaces containing CSF do not exhibit “immunological privilege”
Lymphatic drainage of interstitial fluid from the brain. In the absence of conventional lymphatics in the brain and spinal cord, ISF and solutes, but not cells, drain to cervical lymph nodes along 100-150 nm-thick basement membranes in the walls of cerebral capillaries and cerebral arteries. This route is termed the Intramural Peri-Arterial Drainage (IPAD) pathway. IPAD is almost completely separate from CSF and only 10-15% of solutes leak from IPAD pathways into the CSF. Furthermore, as IPAD pathways are not large enough to allow the direct traffic of inflammatory cells from the brain to cervical lymph nodes, there is “immunological privilege” of the brain; this has implications for Neuroimmunology and diseases such as Multiple Sclerosis.
Age-related impairment of IPAD has important implications for Neurodegenerative diseases, especially Alzheimer’s disease. Soluble Amyloid-β (Aβ) is eliminated from the brain along IPAD pathways. With age changes in the walls of arteries, IPAD is impaired and Aβ is deposited in IPAD pathways as cerebral amyloid angiopathy (CAA) with consequent effects on homoeostasis in the brain.
The relationship between IPAD and the concept of a “gymphatic” system will be discussed.
1. Albargothy NJ, Johnston DA, MacGregor-Sharp M, Weller RO, Verma A, Hawkes CA, Carare RO (2018) Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathologica 136:139-152. doi:10.1007/s00401-018-1862-7
2. Engelhardt B, Vajkoczy P, Weller RO (2017) The movers and shapers in immune privilege of the CNS. Nature Immunology 18:123-131. doi:10.1038/ni.3666