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Abstract
In the absence of conventional lymphatics, drainage of interstitial fluid and solutes from the brain parenchyma to cervical lymph nodes is along basement membranes in the walls of cerebral capillaries and tunica media of arteries. Perivascular pathways are also involved in the entry of CSF into the brain by the convective influx/glymphatic system. The objective of this study is to differentiate the cerebral vascular basement membrane pathways by which fluid passes out of the brain from the pathway by which CSF enters the brain. Experiment 1: 0.5 µl of soluble biotinylated or fluorescent Aβ, or 1 µl 15 nm gold nanoparticles was injected into the mouse hippocampus and their distributions determined at 5 min by transmission electron microscopy. Aβ was distributed within the extracellular spaces of the hippocampus and within basement membranes of capillaries and tunica media of arteries. Nanoparticles did not enter capillary basement membranes from the extracellular spaces. Experiment 2: 2 µl of 15 nm nanoparticles were injected into mouse CSF. Within 5min, groups of nanoparticles were present in the pial-glial basement membrane on the outer aspect of cortical arteries between the investing layer of pia mater and the glia limitans. The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved. The significance of these findings for neuroimmunology, Alzheimer’s disease, drug delivery to the brain and the concept of the Virchow–Robin space are discussed.
Highlights
There are two major extracellular, extravascular fluids associated with the brain, namely CSF in the ventricles and subarachnoid spaces and interstitial fluid (ISF) between cells within the CNS parenchyma
Electron microscope preparations were used to examine the relationship between the extracellular spaces in the mouse hippocampus and basement membranes surrounding capillaries
The basement membrane around capillaries is formed from two elements derived on one side from the astrocytes of the glia limitans and on the other side from capillary endothelium; it is in direct focal contact with the extracellular space of the brain
Summary
There are two major extracellular, extravascular fluids associated with the brain, namely CSF in the ventricles and subarachnoid spaces and interstitial fluid (ISF) between cells within the CNS parenchyma. In most organs of the body, interstitial fluid, metabolites and antigen presenting cells drain to regional lymph nodes along well-defined lymphatic vessels. There are, no conventional lymphatic vessels in the CNS, but there are lymphatic drainage pathways by which CSF and ISF drain to regional lymph nodes. CSF is produced mainly by the choroid plexuses and circulates through the cerebral ventricles and the subarachnoid spaces. Lymphatic drainage of CSF occurs through well-defined channels that traverse the cribriform plate of the ethmoid bone and carry fluid and tracers from the subarachnoid space to lymphatics in the nasal mucosa and to cervical lymph nodes [5]. In larger mammals, including humans, CSF drains directly into the blood
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