In mice, pericyte coverage was reduced to 20% throughout the brain (Figure 3(c))

In mice, pericyte coverage was reduced to 20% throughout the brain (Figure 3(c)). differences in pericyte coverage. Region-specific differences in Risperidone hydrochloride permeability were not associated with disruption of tight junctions but may result from changes in transcytosis across brain endothelial cells. Our data show that certain brain regions are able to maintain low BBB permeability despite substantial pericyte loss and suggest that additional, locally-acting mechanisms may contribute to control of transport. Keywords: BloodCbrain barrier, neurovascular unit, pericytes, extravasation, permeability Introduction The vascular network of the central nervous system (CNS) is responsible for providing an optimal environment within the brain parenchymal space. In addition to its role in nutrient supply, the CNS Rabbit Polyclonal to ALK vasculature is a key component of the bloodCbrain barrier (BBB). The BBB is a multi-cellular structure formed by astrocytes, pericytes, neurons and endothelial cells and is characterized by a low vascular permeability which prevents most blood-borne molecules from entering the brain parenchyma.1,2 The low permeability of the BBB is achieved by the presence of endothelial tight intercellular junctions and a low transcellular diffusion and transcytosis rate.3,4 Interestingly, multiple studies have shown that BBB permeability for specific molecules is heterogeneous throughout the brain.5C8 For example, in rats, brain uptake of insulin is higher in the hippocampus than in the cortex.7 These changes in insulin uptake could not be attributed to differences in insulin receptor expression levels. Additionally, specialized brain regions such as the circumventricular organs9 or the sub-ependymal zone10 also have higher permeability than the rest of the brain, likely due to changes in vesicular transport or tight junction architecture. The signals that regulate such heterogeneous permeability of the BBB during physiological conditions are currently unknown. The permeability of the BBB can be compromised in a brain region-dependent manner during aging or in pathophysiological conditions. In aging, magnetic resonance imaging (MRI) analysis in humans revealed that the BBB is compromised initially in the hippocampus.11 In Alzheimer’s Risperidone hydrochloride disease, BBB permeability is increased in both the hippocampus and the frontal cortex,12 whereas in Fahr’s disease, brain calcification in the basal ganglia Risperidone hydrochloride is linked to BBB disruption.13 In all these conditions, changes in permeability have been associated with pericyte malfunction and reduced pericyte coverage. These results, together with extensive work with mouse models of pericyte depletion,14C16 suggested that pericytes play an important role in controlling BBB permeability. Therefore, we addressed the question whether pericytes are the underlying cause for brain region-specific differences in BBB permeability by using homozygous mice with a mutation in Risperidone hydrochloride the retention motif of pdgf- (mice. In this mouse model, increased BBB permeability did not correlate with the extent of pericyte loss in the different brain regions. Our finding that the regional heterogeneity of Risperidone hydrochloride BBB permeability persists despite the substantial reduction in pericyte coverage suggests that additional, locally-acting mechanisms regulate transport across the BBB. Materials and methods Mice mice used for characterizing BBB permeability of different brain regions were previously described.15,17 We used mice between 11 and 19 months old to measure brain-region specific changes in BBB permeability. Importantly, the pattern of extravasation and/or accumulation was similar between 12 and 19 months old mice (Supplementary Figure 1); 6 and 22 months old mice were only used for biochemical experiments. TauPS2APP (3Tg)??mice used for confirming the localization of endogenous immunoglobulins in the brain parenchyma were previously described.18 Ethical approval for this study was provided by the Federal Food Safety and Veterinary Office of Switzerland. All animal experiments were conducted in strict adherence to the Swiss federal ordinance on animal protection and welfare as well as according to the rules of the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC), and with the explicit approval of the local veterinary authorities (License BS2763 and BS1902). All experiments are reported in compliance.