BRENDA-LEDUCQ

Background

Cerebral small vessel disease (SVD) is a very common progressive vascular disease that covers various pathologies all related to the small vessels in the brain. Due to damage or malfunction of these tiny vessels, the cerebral blood-low is reduced leading to chronic damage of tissue over the years.

SVD is a major cause of microinfarcts and microbleeds-types of stroke that often go undetected, but are major contributors to disability and dementia. Despite such a profound impact on brain health, there are no proven treatments for SVD that can prevent, or slow down the progression of this disease. Treatment is currently limited to reducing common vascular risk factors such as hypertension, diabetes mellitus, hyperlipidemia, and smoking. Additional main risk factors are advanced age and genetic factors.

The underlying pathomechanisms of this disease are still not understood. However, hypertension as the leading risk factor and vascular endothelial dysfunction are clearly associated with cSVD. Brain endothelial cells (BECs) have unique roles at the blood-brain barrier (BBB) and in controlling cerebral blood flow (CBF), including sensing moment-to-moment changes in neural activity. We propose this essential integrator function is progressively degraded in SVD and that microvascular BEC dysfunction serves as a nexus for the loss of brain health.

Yet, we have only scratched the surface in understanding the contribution of BECs to vascular control and brain health. Investigators of this network have identified genetic variants in humans that increase the risk for SVD and stroke. In addition, they have developed mice that express such variants in BECs and have shown that they exhibit SVD and brain injury that mimic those in humans. Our preliminary results suggest that, when combined with genetic variants in BECs, hypertension increases SVD and brain injury to a greater extent than either pathology alone.

Objectives

The BRENDA network aims to investigate the BEC-specific mechanisms underlying SVD, ischemic stroke, and intracerebral hemorrhage. Our overarching hypothesis is that BECs have an initiating role in SVD and that genetic predisposition combined with hypertension synergistically drive SVD (two-hit model).

Our overall objective is to identify novel pathways and targets for treatment, with the goal of preventing the decline in brain health.

We will combine unique complementary expertise to pursue three highly integrated aims:

Aim 1: Define the mechanisms linking risk genes for SVD & stroke to BEC dysfunction and brain injury.

Aim 2: Test the hypothesis that hypertension synergizes with stroke-risk genes to augment BEC dysfunction and brain injury (“two-hit” model).

Aim 3: Unveil the contribution of BEC heterogeneity to vascular function and brain health.

Virtual Seminar Series

December 3, 2024

Endothelial cells of the brain are endowed with neuroprotective blood-brain barrier (BBB) properties that restrict the penetration of blood-borne components into the neural tissue. To ensure brain protection from the earliest developmental steps, neuronal progenitors release Wnt7a/b ligands that restrict brain access to endothelial cells that properly initiate the BBB differentiation cascade. In this talk, the molecular and cellular regulation of this organotypic quality control mechanism will be discussed.

Virtual Seminar Series

October 7, 2024

Dritan Agalliu is interested in the cellular and molecular mechanisms that regulate the formation of the blood-brain barrier in the central nervous system and the mechanisms of barrier breakdown in a variety of CNS diseases. His group has developed novel mouse strains that allows to visualize changes in structural components of the blood-brain barrier, namely tight junctions and caveolae, in living animals for several CNS diseases (e.g. stroke and multiple sclerosis).

Virtual Seminar Series

June 4, 2024

Catherine Hall is interested in how the brain balances energy supply and demand. Small decreases in brain blood flow happen in several diseases and are likely to be important drivers of pathology – for example, in Alzheimer’s disease. They image blood vessels in brain slices and in vivo, in behaving mice, while manipulating neuronal activity. Together these measurements provide a rich understanding of how the brain changes at the onset of disease or when oxygen supply is reduced.

Virtual Seminar Series

May 7, 2024

Cerebral Cavernous Malformation (CCM) is a disease in which abnormally dilated and tortuous blood vessels form vascular malformations predominantly in the brain. About 9% of patients also suffer from vascular malformations in the skin. Konstantin and his team developed for the first time a mouse model of CCM skin lesions that allows to study disease mechanisms at single cell resolution in living animals in real time. It also opens exciting possibilities as it, for example, permits, to investigate the effects of potential drugs on lesion growth or lesion regression.

News Archive 2023

2024

2023

Kopczak A, Stringer MS, van den Brink H, Kerkhofs D, Blair GW, van Dinther M, Reyes CA, Garcia DJ, Onkenhout L, Wartolowska KA, Thrippleton MJ, Kampaite A, Duering M, Staals J, Lesnik-Oberstein S, Muir KW, Middeke M, Norrving B, Bousser MG, Mansmann U, Rothwell PM, Doubal FN, van Oostenbrugge R, Biessels GJ, Webb AJS, Wardlaw JM, Dichgans M; TREAT-SVDs collaborators. Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial. Lancet Neurol. 2023 Nov;22(11):991-1004. doi: 10.1016/S1474-4422(23)00293-4.

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