Pathways of communication between the subarachnoid space and the brain parenchyma. Are they relevant to neurodegenerative diseases?

Introduction Accumulation of the β-amyloid (Aβ) protein in cerebral blood vessels is a hallmark of Alzheimer’s disease. Identifying the factors that contribute to this accumulation is critical for both prevention and treatment of the disease. Previous studies have shown that Aβ from the parenchyma is removed along the basement membranes of capillaries and arteries towards the surface of the brain. Aβ is present in the cerebrospinal fluid (CSF) of the brain and there have been suggestions that Aβ is entering the parenchyma and eliminated back into the CSF. The precise anatomical routes by which CSF moves into and out of the brain parenchyma have not been identified. The aim of this study was to determine the entry route and the distribution of solutes and particulate matter in the brain at two time points following its injection into the CSF and investigate age-related changes in CSF influx and distribution.Materials and method Evans blue dye (EBD), anti-sense oligonucleotides (ASO), fluorescently-tagged Aβ40 and nanoparticles were injected into cisterna magna of adult male C57BL/6J mice and mice were sacrificed at 5 or 30 minutes after injection (n = 3 /group). Representative sections across the brain were immunostained for the detection of basement membranes and smooth muscle actin to differentiate arteries from veins by confocal microscopy. Nanoparticles were detected using transmission electron microscopy.Results and discussion Within 5 minutes after injection, EBD, ASO, nanoparticles and Aβ entered the brain along the pial – glial vascular basement membranes. In 6 – 10 week old mice, soluble Aβ colocalised with the astrocytic basement membrane marker (α-2 laminin) and collagen IV of leptomeningeal and cortical arteries. After 30 minutes, Aβ was present in the tunica media of leptomeningeal and cortical arteries. The depth of Aβ along the artery wall in the parenchyma was significantly higher at 30 min compared to 5 min post-injection. Regional differences between the cortical, subcortical and posterior brain regions were also detected. In 24 – 30 month old mice, Aβ also entered along the pial – glial basement membrane of arteries after 5 min. However, after 30 min, Aβ was also present in 1) the basement membrane of capillaries, veins, 2) the tunica media of arteries, 3) diffusely in the parenchyma where it was taken up by astrocytes, neurons and macrophages.Conclusions These results indicate that the entry route of CSF is along the pial – glial basement membrane of arteries at 5 min post-injection. Solutes in the CSF appear to enter the intramural periarterial drainage pathway after 30 min for clearance back into the CSF. The normal flow of CSF along the basement membrane of arteries in old mice is impaired. These data may contribute to the understanding of Aβ deposition in walls of arteries as cerebral amyloid angiopathy and provide an insight into the intrathecal delivery route for treatment of neurodegenerative diseases including Alzheimer’s disease