The Blood-Brain-Barrier (BBB) is an important feature of blood vessels to protect the central nervous system (CNS) from toxic or possible harmful substances circulating in the bloodstream. In the circumventricular organs (CVOs) which are small brain areas, located in the midline around the third and fourth ventricle physiologically, there is no vascular BBB established. Although this seems to be contradictory at first, a second look reveals that the CNS has to be in contact with the bloodstream in these specialised brain areas to exchange information between these compartments. Therefore, the CVOs are also called communication points between blood and brain and categorised into sensory and secretory organs according to their physiological function. In the project funded by the German Research Council with in the Research Group FOR2325, we are interested in the molecular mechanisms that regulate the absence of BBB properties within CVO vessels and how modulation of vascular barrier function influences the communication of the brain with the blood, hence with peripheral organs such as the kidney.
Supported by the Deutsche Forschungsgemeinschaft (DFG) research group FOR2325, “The Neurovascular Interface” LI 911/5-1.
Due to their role in regulating homeostatic body function, CVO research is increasingly recognized by the scientific community.
Regulation of BBB genes in epilepsy
Mesial temporal lobe epilepsy (MTLE) is the most common form of refractory epilepsy, characterized by spontaneous recurrent seizures. Functional impairment of the blood-brain barrier (BBB) has been attributed to contribute to the formation and/or progression of the disease. However, a detailed knowledge of the molecular changes at the BBB and the neurovascular unit (NVU) is currently missing. In the project funded by the government of Hesse (LOEWE-CePTER consortium), aims to characterise in detail the effects of MTLE on brain microvessels and endothelial cells. To characterize BBB properties in MTLE, we will isolate microvessel fragments, of morphologically unaffected cortex and epileptic and sclerotic hippocampus tissue of MTLE patients and compare their transcriptome by next gemeration sequencing (NGS). To examine the role of identified target genes on the BBB, we will overexpress and silence the genes in the expressing cell type of the NVU. We will further test modified cells for their BBB relevant function in co-cultures and by transendothelial electrical resistance (TEER) measurements in vitro.
Supported by the LOEWE-Centre CePTER - Center for Personalized Translational Epilepsy Research.
Brain endothelial cells (ECs) of the blood-brain barrier (BBB) maintain brain homeostasis via paracellular tight-junctions and specific transporters such as P-glycoprotein. The BBB is responsible for negligible bioavailability of many neuroprotective drugs. In Alzheimer’s disease (AD):
• 80% of cases display cerebral amyloid angiopathy (CAA).
• CAA present deposition of amyloid-β (Aβ) at the blood vessels.
• The source of perivascular Aβ however is not entirely clear.
• Current treatment approaches include inhibitors of beta-secretase 1 (BACE-1), the rate limiting of two proteinases generating neurotoxic Aβ.
• BACE-1 is highly expressed in endosomes and membranes of neurons and glia.
We have shown that BACE-1 is also expressed by brain ECs and potentially contributes to CAA formation and AD pathogenesis (Devraj et al., 2016). We therefore hypothesize that BACE-1 at the BBB might be involved in the cleavage of circulating and/or neuronal amyloid precursor protein (APP), thus generating Aβ locally at the BBB. Hence, targeting BACE-1 at the BBB may lead to novel AD therapeutics.
This project is included in the European Training Network H2020-MSCA-ITN-2015, BtRAIN.
BtRAIN (H2020-MSCA-ITN-2015 675619)
Supported by the HORIZON2020 The Marie Skłodowska-Curie actions, Innovative TRaining Natwork - BtRAIN.
Cell fate decision in the hematopoietic system
Although the Wnt/β-catenin pathway has been intensively studied in the last decades, its role in cell fate decision during haematopoietic differentiation and specifcally, with regard to myeloproliferative neoplasms is incompletely understood. It was reported that „gain of function“ (GOF) of β-catenin in all haematopoietic cells in mice induced anaemia, thrombocytopenia, impaired megakaryocyte (MK)-maturation and faster cell cycle entry of haematopoietic stem cells (HSCs) in vivo (Scheller et al., 2006). In contrast, application of Wnt-ligands on fetal liver cells in vitro increases MK-differentiation and –maturation (Macaulay et al., 2013). In order to understand the role of the Wnt-pathway specifically in MKs, we use transgenic mouse lines and hematopoietic cell lines to investigate whether activation of the Wnt-pathway in specific branches or bifurcation points in the haematopoietic system effects cell fate decision. Particularly, we intend to understand if a constitutively active form of β-catenin favors MK differentiation, providing new insight in megakaryopoiesis and myeloproliferative neoplasms.
Supported by the Deutsche Forschungsgemeinschaft (DFG), project LI 911/7-1 "The role of Wnt/β-catenin signaling for megakaryocytic cell fate decision".
Institute of Neurology (Edinger-Institute) University Hospital, Goethe University Frankfurt Heinrich-Hoffmann-Str. 7 Building 89, 4.Floor, R402 60528 Frankfurt/Main, Germany