Abstract:

The blood-brain barrier (BBB) (discovered and defined by Max Lewandowsky and Lina Stern, and not, as it is universally, and yet erroneously believed, by Paul Ehrlich (Verkhratsky and Pivoriunas, 2023)) that separates the nervous system from the circulation is evolutionarily conserved from arthropods to man. The primeval BBB of the invertebrates and some early vertebrates was made solely by glial cells and secured (in invertebrates) by septate junctions; in most vertebrates, including mammals, the barrier is associated with endothelial cells and secured with tight junctions. This, however, is a simplified view, as brain-fluid barriers in general and the BBB in particular, are complex structures, which dynamically control traffic between nervous tissue and the circulation. The vascular part of the BBB complex (Figure 1) includes hemocompatible glycocalyx, which outlines and protects the single-cell layer of brain endothelial cells (BECs) clamped together with tight and adherence junctions that restrict paracellular transport. Tight junctions form a highly efficient barrier for ion fluxes that translates into a very high (up to 5000 Ω/cm2) electrical resistance (generally referred to as transendothelial electrical resistance or TEER) of the brain endothelial barrier, which is > 100 times larger as compared to peripheral capillaries where TEER varies between 2 and 20 Ω/cm2. Brain endotheliocytes are in direct contact with pericytes, several subtypes of which are associated with capillaries and pre- and post-capillary vessels. Pericytes and endothelial cells are covered with the vascular basement membrane. In arterioles and venules, the basement membrane is surrounded by smooth muscle cells regulating vasodilatation and vasoconstriction. The parenchymal part of the BBB is made by endfeet of protoplasmic (in grey matter) or fibrous (in white matter) astrocytes; every protoplasmic astrocyte extends at least one (and usually several) perivascular processes (Hosli et al., 2022). Astrocytic endfeet rest on the parenchymal basement membrane; together they form the glia limitans perivascularis (which also includes processes of juxtavascular microglia). The composition of vascular and parenchymal basal membranes is different, reflecting distinct extracellular matrix components secreted by endotheliocytes and astrocytes. At the level of arterioles and venules, vascular and parenchymal membranes are separated by perivascular space filled with cerebrospinal fluid; this perivascular space, together with glia limitans, provides the anatomical substrate for the brain-wide glymphatic system. At the level of capillaries, both basement membranes join while perivascular space disappears.