Synthesis and localization of plasma proteins in the developing human brain. Integrity of the fetal blood-brain barrier to endogenous proteins of hepatic origin

Abstract

The distribution and possible origins of plasma proteins in the human embryonic and fetal brain at different stages of development have been investigated by a combination of isolation and translation of mRNAs and immunocytochemistry using specific antisera. As many as 23 plasma-like proteins have been identified using immunocytochemical methods at the light microscopical level. The presence of mRNAs for 13 of the immunocytochemically positive plasma proteins was demonstrated by in vitro and in ovo translation followed by crossed immunoelectrophoresis and autoradiography; this indicates in situ synthesis of these proteins (e.g., alpha-fetoprotein, alpha 1-antitrypsin, GC-globulin, alpha 2-macroglobulin, pseudocholinesterase, and transferrin) in some brain regions. The regional distribution of some proteins and the absence of some mRNAs suggest that the presence of certain plasma proteins in developing brain may be accounted for by uptake from csf or via nerve processes extending beyond the blood-brain barrier. In several cases, specific proteins appear to be associated with defined cell types, e.g., alpha-fetoprotein, GC-globulin, and ceruloplasmin with neurons, alpha 2-macroglobulin with endothelial cells, and ferritin with glial cells. Some proteins were associated with two or three cell types, e.g., alpha 1-antitrypsin with neurons and glia, and transferrin and alpha 2HS-glycoprotein with neurons, glia, and endothelial cells. Comparison of the expression of mRNAs from fetal brain and liver injected into Xenopus oocytes showed that a few proteins (transferrin and ceruloplasmin) were secreted when liver mRNA was injected, but not when brain mRNA was injected. This suggests that there may be an important difference in the structure and/or processing of these proteins in the brain which may reflect a function different from that associated with them when they originate from the liver. Staining was generally intracellular rather than extracellular; plasma proteins were not associated with the areas immediately around blood vessels although there was a strong immunoprecipitation for each protein within the lumen of cerebral blood vessels. These immunocytochemical findings together with the identification of mRNAs for a large number of plasma proteins in immature brain are discussed in relation to animal experimental work which suggests that the blood-brain barrier to protein is present even at very early stages of brain development.