Brain barriers and brain fluid research in 2016: advances, challenges and controversies

Abstract This editorial highlights some of the advances that occurred in relation to brain barriers and brain fluid research in 2016. It also aims to raise some of the attendant controversies and challenges in such research.http://deepblue.lib.umich.edu/bitstream/2027.42/136059/1/12987_2017_Article_52.pd

The year in review: progress in brain barriers and brain fluid research in 2018

Abstract This editorial focuses on the progress made in brain barrier and brain fluid research in 2018. It highlights some recent advances in knowledge and techniques, as well as prevalent themes and controversies. Areas covered include: modeling, the brain endothelium, the neurovascular unit, the blood–CSF barrier and CSF, drug delivery, fluid movement within the brain, the impact of disease states, and heterogeneity.https://deepblue.lib.umich.edu/bitstream/2027.42/147737/1/12987_2019_Article_124.pd

Brain Endothelial Cell-Cell Junctions: How to “Open” the Blood Brain Barrier

The blood-brain barrier (BBB) is a highly specialized structural and biochemical barrier that regulates the entry of blood-borne molecules into brain, and preserves ionic homeostasis within the brain microenvironment. BBB properties are primarily determined by junctional complexes between the cerebral endothelial cells. These complexes are comprised of tight and adherens junctions. Such restrictive angioarchitecture at the BBB reduces paracellular diffusion, while minimal vesicle transport activity in brain endothelial cells limits transcellular transport. Under normal conditions, this largely prevents the extravasation of large and small solutes (unless specific transporters are present) and prevents migration of any type of blood-borne cell. However, this is changed in many pathological conditions. There, BBB disruption (“opening”) can lead to increased paracellular permeability, allowing entry of leukocytes into brain tissue, but also contributing to edema formation. In parallel, there are changes in the endothelial pinocytotic vesicular system resulting in the uptake and transfer of fluid and macromolecules into brain parenchyma. This review highlights the route and possible factors involved in BBB disruption in a variety of neuropathological disorders (e.g. CNS inflammation, Alzheimer’s disease, Parkinson’s disease, epilepsy). It also summarizes proposed signal transduction pathways that may be involved in BBB “opening”

White matter T2 hyperintensities and blood‐brain barrier disruption in the hyperacute stage of subarachnoid hemorrhage in male mice: The role of lipocalin‐2

AimsThe current study examined whether white matter injury occurs in the hyperacute (4 hours) phase after subarachnoid hemorrhage (SAH) and the potential role of blood‐brain barrier (BBB) disruption and an acute phase protein, lipocalin 2 (LCN2), in that injury.MethodsSubarachnoid hemorrhage was induced by endovascular perforation in adult mice. First, wild‐type (WT) mice underwent MRI 4 hours after SAH to detect white matter T2 hyperintensities. Second, changes in LCN2 expression and BBB disruption associated with the MRI findings were examined. Third, SAH‐induced white matter injury at 4 hours was compared in WT and LCN2 knockout (LCN2 KO) mice.ResultsAt 4 hours, most animals had uni‐ or bilateral white matter T2 hyperintensities after SAH in WT mice that were associated with BBB disruption and LCN2 upregulation. However, some disruption and LCN2 upregulation was also found in mice with no T2‐hyperintensity lesion. In contrast, there were no white matter T2 hyperintensities in LCN2 KO mice after SAH. LCN2 deficiency also attenuated BBB disruption, myelin damage, and oligodendrocyte loss.ConclusionsSubarachnoid hemorrhage causes very early BBB disruption and LCN2 expression in white matter that is associated with and may precede T2 hyperintensities. LCN2 deletion attenuates MRI changes and pathological changes in white matter after SAH.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151855/1/cns13221.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151855/2/cns13221_am.pd

Na+ and K+ ion imbalances in Alzheimer's disease

AbstractAlzheimer's disease (AD) is associated with impaired glutamate clearance and depressed Na+/K+ ATPase levels in AD brain that might lead to a cellular ion imbalance. To test this hypothesis, [Na+] and [K+] were analyzed in postmortem brain samples of 12 normal and 16 AD individuals, and in cerebrospinal fluid (CSF) from AD patients and matched controls. Statistically significant increases in [Na+] in frontal (25%) and parietal cortex (20%) and in cerebellar [K+] (15%) were observed in AD samples compared to controls. CSF from AD patients and matched controls exhibited no differences, suggesting that tissue ion imbalances reflected changes in the intracellular compartment. Differences in cation concentrations between normal and AD brain samples were modeled by a 2-fold increase in intracellular [Na+] and an 8–15% increase in intracellular [K+]. Since amyloid beta peptide (Aβ) is an important contributor to AD brain pathology, we assessed how Aβ affects ion homeostasis in primary murine astrocytes, the most abundant cells in brain tissue. We demonstrate that treatment of astrocytes with the Aβ 25–35 peptide increases intracellular levels of Na+ (~2–3-fold) and K+ (~1.5-fold), which were associated with reduced levels of Na+/K+ ATPase and the Na+-dependent glutamate transporters, GLAST and GLT-1. Similar increases in astrocytic Na+ and K+ levels were also caused by Aβ 1–40, but not by Aβ 1–42 treatment. Our study suggests a previously unrecognized impairment in AD brain cell ion homeostasis that might be triggered by Aβ and could significantly affect electrophysiological activity of brain cells, contributing to the pathophysiology of AD

Glutamine Uptake at the Blood-Brain Barrier Is Mediated by N-System Transport

The mechanism of unidirectional transport of glutamine from blood to brain in pentobarbital-anesthetized rats was examined using in situ perfusion. Amino acid uptake into brain across the blood-brain barrier (BBB) is classically thought to be via the Na-independent large neutral (L-system), acidic and basic amino acid transporters. In the presence of physiological concentrations of amino acids in the perfusate, which should saturate the known amino acid transporters at the BBB, the cortical transfer constant ( K i ) for l-[ 14 C]glutamine was 11.6 ± 1.1 µl/g/min. The addition of either 10 m M 2-amino-2-norbornanecarboxylic acid or 10 m M 2-amino-2-norbornanecarboxylic acid and 5 m M cysteine had no effect on the cortical K i for l-[ 14 C]glutamine, indicating that glutamine transport under these conditions does not occur by the L-, A-, or ASC-systems. Decreasing perfusate Na from 140 to 2.4 m M by Tris substitution reduced the cortical K i for l-[ 14 C]glutamine by 62% ( p ≤ 0.001). The Na-dependent uptake has the characteristics of N-system transport. It was inhibited by l-histidine and l-glutamine, both N-system substrates, and it was pH sensitive and moderately tolerant of Li substitution for Na. This putative N-system transporter at the luminal membrane of the BBB plays an important role in mediating brain glutamine uptake.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65581/1/j.1471-4159.1998.71062565.x.pd

Vascular disruption and blood–brain barrier dysfunction in intracerebral hemorrhage

Abstract This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood–brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer’s disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke.http://deepblue.lib.umich.edu/bitstream/2027.42/134526/1/12987_2014_Article_103.pd

Activation of epiplexus macrophages in hydrocephalus caused by subarachnoid hemorrhage and thrombin

AimsWe have found that hydrocephalus development in spontaneously hypertensive rats was associated with activation of epiplexus cells. The current study examined whether epiplexus cell activation occurs in a rat subarachnoid hemorrhage (SAH), whether activation would be greater in a subset of rats that developed hydrocephalus and the potential role of thrombin in epiplexus cell activation.MethodsThere were two parts in this study. First, an endovascular perforation was performed in rats to induce SAH. Second, rats received an intraventricular infusion of either thrombin or saline. Magnetic resonance imaging was used to measure the ventricular volumes. Immunofluorescence and immunohistochemistry were used to study epiplexus cell activation.ResultsIba‐1, OX‐6, and CD68 were expressed in the epiplexus cells of the choroid plexus in sham‐operated rats. SAH increased Iba‐1 and CD68 immunoreactivity in epiplexus cells in addition to an increase in Iba‐1‐positive cell soma size. Those effects were greater in rats that developed hydrocephalus. Intraventricular thrombin mimicked the effects of SAH on epiplexus cell activation and hydrocephalus.ConclusionThis study supports the concept that epiplexus cell activation is associated with hydrocephalus development. Epiplexus cell activation may be in response to thrombin production after hemorrhage, and it may be a therapeutic target.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151813/1/cns13203_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151813/2/cns13203.pd

PEPT2-Mediated Uptake of Neuropeptides in Rat Choroid Plexus

Purpose . The peptide transporter PEPT2 was recently shown to be functionally active in rat choroid plexus, suggesting that it may play a role in neuropeptide homeostasis in the cerebrospinal fluid. This study, therefore, examined the role of PEPT2 in mediating neuropeptide uptake into choroid plexus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41485/1/11095_2004_Article_302748.pd