TY - JOUR

T1 - Vascular basement membranes as pathways for the passage of fluid into and out of the brain

AU - Morris, Alan W.J.

AU - Sharp, Matthew Mac Gregor

AU - Albargothy, Nazira J.

AU - Fernandes, Rute

AU - Hawkes, Cheryl A.

AU - Verma, Ajay

AU - Weller, Roy O.

AU - Carare, Roxana O.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - Amyloid-β

KW - Arteries

KW - Basement membranes

KW - Capillaries

KW - Drug delivery

KW - Lymphatic drainage

KW - Nanoparticles neuroimmunology

KW - Virchow–Robin space

U2 - 10.1007/s00401-016-1555-z

DO - 10.1007/s00401-016-1555-z

M3 - Journal article

C2 - 26975356

AN - SCOPUS:84961167095

VL - 131

SP - 725

EP - 736

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 5

ER -