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Mechanisms of regulation of the blood-brain barrier; towards opening and closing the barrier on demand

Final Report Summary - BBBARRIER (Mechanisms of regulation of the blood-brain barrier; towards opening and closing the barrier on demand.)

The BBBARRIER project aims at providing new insights into the role(s) of the brain vasculature’s different cell types – in particular the pericytes - in the execution and regulation of the blood-brain barrier (BBB). The BBB protects the brain from harmful substances in the blood, but also blocks the passage of potentially helpful drugs into the brain to combat brain diseases such as Alzheimer’s disease and glioblastoma. In the project, we have analyzed mice with a diminished number of pericytes in the brain’s blood vessels, which, as a consequence, display a BBB that is partially opened for passage of substances from the blood to the brain. Some of the substances found to passage the pericyte-less BBB, including antibodies, might be exploited as drugs. We have sought the molecular mechanisms for how pericytes regulate the BBB differentiation of other vascular cell types, e.g. endothelial cells and astrocytes. In the course of this work, we realized that we were lacking fundamental insights into the molecular and cellular building blocks of the BBB. We therefore initiated a study to reveal, as exactly as possible, the gene expression patterns of the different vascular and perivascular cell types that compose the brain vasculature at different levels of the arteriovenous hierarchy. Using a new technology referred to as single cell RNA sequencing (scRNASeq) we have generated a highly detailed molecular atlas of the brain vasculature. Using this information as reference, we have begun analyzing the changes that take place at the BBB as pericytes disappear, or stop functioning, resulting in BBB opening for selective passage of certain compounds. Our data thereby shed light on the molecular composition of the BBB and how opening of the BBB might be used for drug delivery into the brain. In a second aim, our work aimed at exploring the putative negative – pathological – consequences of loss of brain pericytes and opening of the BBB. Here we made a surprising and serendipitous finding, namely that the same genes known to be involved in pericyte recruitment to blood vessels during development, were mutated in a rare human genetic disease called primary familial brain calcification (PFBC). PFBC is characterized by the formation of calcium phosphate depositions along the microvessels in deep brain regions, and has a spectrum of clinical neurological manifestations. We found that pericyte- and BBB-deficient mouse models developed brain calcification similar to human PFBC patients, and studied both the functional consequences of the gene mutations found in PFBC patients and the appearance, growth and composition of the calcifications. In summary, our project has advanced our understanding of the cellular and molecular composition and regulation of the BBB, and how defects in the signaling molecules that are normally engaged in pericyte recruitments lead to calcification of small blood vessels in the brain.