Background:
Small vessel disease (SVD) is a prevalent disorder of the brain’s microvessels and a common cause of dementia and stroke. Recent evidence suggests a key role involving features of normal ageing in disease development and progression, including endothelial activation, pericyte dysfunction, blood-brain barrier (BBB) failure, and a chemotactic microglia response. Here, we aim to examine this relationship through a series of translational investigations.
Methods:
Using spinning-disk confocal and multispectral microscopy, we first quantified pericyte coverage and endothelial activation (VCAM-1 expression) in young and aged C57Bl/6J mice, and in young controls, mild and severe SVD cases, respectively. Secondly, pericyte and endothelial fluid biomarkers were analysed in a mild and non-disabling stroke cohort, correlating them with SVD MRI markers and cognition. Thirdly, we employed a novel adeno-associated virus (AAV) exclusively targeting brain endothelial cells to overexpress (OE) Vcam1, Icam1, Selp and Sele in mice, shedding light on endothelial activation’s role in pericyte dysfunction and BBB breakdown, but also the reciprocal influences with the microglial response. Finally, we used an innovative mouse model allowing the genetic manipulation of brain pericytes specifically (Atp13a5-CreER), offering insights into their biological impact on neighbouring cells and BBB functions.
Results:
Both aged mice and SVD cases exhibited a significant reduction in pericyte coverage and increase in VCAM-1 expression in microvessels ( 10 m in diameter). Biomarker analyses revealed associations between PDGFRB, PDGF-BB, ICAM-1, VCAM-1, and E-selectin concentrations with specific SVD manifestations. Preclinical AAV experiments highlighted correlations between endothelial activation, pericyte dysfunction, reduced brain perfusion, and BBB breakdown, with distinct immune responses observed in AAV-Vcam1OE and AAV-Icam1OE groups. The brain pericyte-specific mouse model unveiled diverse pericyte subtypes along the vascular tree, emphasizing their importance in microvascular dynamics. Capillary endothelial cells rapidly acquired a pro-inflammatory signature upon genetic ablation of brain pericytes.
Conclusion:
Our multifaceted approach highlights the crucial role of endothelial-pericyte crosstalk in vascular dementia progression. The integration of post-mortem brain tissues, fluid biomarkers, viral manipulations, and innovative mouse models enriches our understanding of the tripartite crosstalk, paving the way for potential therapeutic interventions in vascular dementia.
SPEAKER BIOGRAPHY
Dr Axel Montagne joined the UK Dementia Research Institute at Edinburgh in 2020. He completed his PhD degree at the University of Caen Normandy (France), followed by postdoctoral training at the University of Southern California (USC) in Los Angeles. Axel rapidly became Assistant then Associate Professor at USC in 2016 and 2020, respectively. His career has focused on how cerebrovascular dysfunctions contribute to neurodegeneration and dementia in both animal models and humans. In his UK DRI program, he combines molecular approaches with rodent non-invasive imaging, particularly MRI and microscopy techniques, to study the causes and effects of blood-brain barrier (BBB) dysfunction, with a particular focus on the Endothelium-Pericyte-Immune tripartite interactions, in the context of neurodegenerative disease. Dr Montagne’s work is supported by the UK DRI, principally funded by the UK Medical Research Council (MRC), and additional funding partners (Alzheimer’s Research UK, Alzheimer’s Society UK, and British Heart Foundation). In addition, Dr Montagne was awarded the 2021 SCOR Young European Researcher Prize for his research into Alzheimer’s disease and a MRC Career Development Award in 2022.
