A great many aspects of neuronal physiology and pathology involve or affect the brain barriers. Recent insights into the role of the blood–brain barrier during development, and advances in our understanding of how it affects neurological disorders, have led to closer links between the two topics.

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Engaging neuroscience to advance translational research in brain barrier biology

The health of the vertebrate brain is dependent on appropriate levels of cerebrospinal fluid (CSF), which is secreted by the choroid plexus (ChP). In this Review, Lehtinen and colleagues examine ChP structure and development and explore recently discovered functions of the ChP–CSF system.

Development and functions of the choroid plexus-cerebrospinal fluid system

Transferrin, biochemistry, physiology and clinical significance

Iron is an important constituent in brain and, in certain regions, e.g., the basal nuclei, reaches concentrations equivalent to those in liver. It has a role in electron transfer and is a cofactor for certain enzymes, including those involved in catecholamine and myelin synthesis. Iron in CSF is likely to be representative of that in interstitial fluid of brain. Transferrin in CSF is fully saturated, and the excess iron may be loosely bound as Fe(II). Brain iron is regulated in iron depletion, suggesting a role for the blood-brain barrier (BBB). Iron crosses the luminal membrane of the capillary endothelium by receptor-mediated endocytosis of ferric transferrin. This results in an initial linear uptake of radioactive iron into brain at an average rate relative to serum of about 3.3 x 10(-3) ml x g of brain(-1) x h(-1) in the adult rat. This corresponds to about 80 nmol x kg(-1) x h(-1). Much higher rates occur in the postnatal rat. These increase during the first 15 days of life and decline thereafter. Within the endothelium, most of the iron is separated from transferrin, presumably by the general mechanism of acidification within the endosome. Iron appears to be absorbed from the vesicular system into cytoplasm and transported across the abluminal plasma membrane into interstitial fluid as one or more species of low molecular weight. There is some evidence that ionic Fe(II) is involved. Certainly Fe(II) ions presented on the luminal side rapidly cross the complete BBB, i.e., luminal and abluminal membranes. Within interstitial fluid, transported iron will bind with any unsaturated transferrin synthesized or transported into the brain-CSF system. Oligodendrocytes are one site of synthesis. From interstitial fluid, ferric transferrin is taken up by neurones and glial cells by the usual receptor-mediated endocytosis. Calculations of the amount of iron leaving the system with the bulk flow of CSF indicate that most iron entering brain across the capillary endothelium finally leaves the system with the bulk outflow of CSF through arachnoid villi and other channels. A system in which influx of iron into brain is by regulated receptor-mediated transport and in which efflux is by bulk flow is ideal for homeostasis of brain iron.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.1997.69020443.x

Transport of iron in the blood-brain-cerebrospinal fluid system

Timely and adequate iron acquisition by the brain is essential to normal neurological function. Despite the numerous cognitive and neurological impairments that are associated with disruptions in brain iron acquisition, including both too much and too little iron, the mechanism and regulation of the mechanisms by which the brain acquires iron are poorly understood. In this article, we review the current state of knowledge regarding expression of iron transport proteins in the brain, brain iron uptake and discuss why a model for brain iron uptake must take into consideration the potentially competing influences on the endothelial cell between the status of iron in the brain versus the systemic iron status.

Brain iron uptake and homeostatic mechanisms: an overview

1. The concentration of total protein in c.s.f. and plasma has been measured in fetal sheep of different gestational ages and in the adult. In c.s.f. it was highest (approximately 840 mg/100 ml.) in the youngest fetuses (35 days) and declined steeply by 60 days (260 mg/100 ml.). It decreased less markedly in the last half of gestation to reach about 50 mg/100 ml. at 125 days which is twice the adult value. Protein concentration in plasma was lowest in the youngest fetuses and did not rise much until the second half of gestation during which time it doubled. There was a further rather larger increase between the late fetal (125 days) stage and the adult.2. Albumin, fetuin, alpha-fetoprotein (AFP), transferrin and lipoprotein were identified in c.s.f. and plasma.3. The concentrations of albumin, AFP and fetuin in c.s.f. and plasma at different gestational ages were measured using immunodiffusion and radioimmuno-assays.4. Albumin was the major protein in plasma at all ages studied (35-128 days gestation and adult). Its concentration increased throughout gestation whereas that of fetuin was similar at all fetal ages and that of AFP declined markedly during the second half of gestation. In the adult, fetuin was only about 0.1% of the total protein in plasma and AFP was not detectable.5. In 35-40 day fetuses albumin, AFP and fetuin accounted for 90% of the total protein concentration in plasma and for about 70-80% of the total protein concentration of c.s.f. As gestation progressed the concentration of all three proteins in c.s.f. declined. But the concentration of AFP and fetuin fell more rapidly and to a greater extent than that of albumin; neither AFP nor fetuin could be detected in adult c.s.f.6. The c.s.f.: Plasma ratio was above 50% for AFP and above 60% for fetuin at 35 days compared with about 25% for albumin at the same fetal age. The c.s.f.: plasma ratios for all three proteins declined with increasing fetal age and were not significantly different from each other by about mid gestation.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1980.sp013171

Proteins in cerebrospinal fluid and plasma of fetal sheep during development.

1. Plasma proteins have been demonstrated to be present in early fetal sheep brain in amounts which cannot be accounted for by blood contamination. 2. The distribution of alpha-fetoprotein, albumin, fetuin, alpha 1-antitrypsin and transferrin has been studied by immunoassay of extracts from brain homogenates and by immunoperoxidase histochemistry of fetal brains between 37 and 125 days gestation (term is 150 days). 3. At 35 days gestation fetuin and albumin were quantitatively the most important proteins in fetal brain, both as estimated by extraction and by immunohistochemistry. Both of these proteins, and also alpha-fetoprotein and alpha 1-antitrypsin, declined considerably in amount by 60 days gestation. After 60 days the concentrations of albumin and alpha-fetoprotein were not significantly different from that due to blood contamination and only occasional cells could be demonstrated by immunohistochemistry. Fetuin and alpha 1-antitrypsin were present in reduced but significant amounts at least up to 125 days gestation. 4. The immunohistochemical results showed that considerable numbers of immature neurones were stained for some plasma proteins. Fetuin positive cells predominated both in terms of the larger number of cells which stained at 35-40 days gestation and in the persistence of positive cells up to 125 days gestation. Numerous cells in the neuroependymal layer and in several layers of the developing cortical plate were positive, especially early in gestation. Only a few transferrin or alpha 1-antitrypsin positive cells were observed. 5. Permeability of the blood-brain barrier to sheep or human serum albumin (labelled with 125I) was tested in 60 day fetal sheep by intravenous injection and estimation of brain radioactivity at 3 or 6 hr with allowance for blood contamination. Only a very small (but significant) penetration of protein was detected. Unlike penetration of protein into c.s.f. at the same age, it did not reach its natural steady state in brain. 6. It is concluded that the blood-brain barrier to protein is well developed in the immature fetal sheep but that developing neurones probably acquire certain plasma proteins directly from the c.s.f. when they are differentiating in the neuroependyma. The subsequent distribution of plasma protein positive cells in different brain regions is suggested to be due to the migration of developing neurones for the neuroependyma although the possibility of local synthesis of plasma proteins has not been excluded.

Plasma proteins in fetal sheep brain: blood-brain barrier and intracerebral distribution.

The concentrations of total protein, α-fetoprotein, fetuin, transferrin and albumin have been measured in cerebrospinal fluid (CSF) and plasma of fetal pigs from 26 to 109 days gestation. Plasma total protein concentration was lowest in the youngest fetuses but thereafter it was between 1,500 and 2,200 mg/100 ml. α-Fetoprotein was the predominant plasma protein early in development but its concentration declined throughout the fetal period. α-Fetoprotein, fetuin and transferrin accounted for over 65% of the total protein concentration at all fetal ages. Albumin was not detectable in either plasma or CSF at 26 days and did not account for more than 10% of total plasma protein concentration at later stages of gestation; in contrast fetuin was the major protein in plasma (and CSF) later in fetal development. In CSF the concentration of fetuin was highest (178 ± 8 mg/100 ml) at 26 days. The concentrations of total protein (961 ± 95 mg/100 ml), α-fetoprotein (406 ± 77 mg/100 ml) and transferrin (195 ± 19 mg/100 ml) were highest at 31 days after which the concentration of all the main proteins fell very considerably. Albumin was first detected in CSF at 38 days and contributed less than 10% of total protein concentration at later fetal ages. Possible origins of plasma proteins in fetal CSF are discussed. Differences in CSF: plasma ratios for different proteins are consistent with a specific transfer mechanism between their two compartments; but synthesis by fetal choroid plexus or brain has not been excluded.

Proteins in cerebrospinal fluid and plasma of fetal pigs during development.

The concentration of AFP in the plasma of fetal pigs was highest in early gestation (Days 15-30) and declined with advancing gestation. This pattern was comparable to those observed in other mammals with similar lengths of gestation. In contrast, allantoic and amniotic fluid AFP concentrations were highest during the middle third of gestation but these concentrations were much lower than those in fetal plasma throughout gestation. The allantois appears to be a significant distribution space for AFP in early gestation.

F. L. Lorscheider

Papers

Proteins in cerebrospinal fluid and plasma of fetal sheep during development.

Plasma proteins in fetal sheep brain: blood-brain barrier and intracerebral distribution.

Proteins in cerebrospinal fluid and plasma of fetal pigs during development.

Distribution of alpha-fetoprotein in fetal plasma and in amniotic and allantoic fluids of the pig