Title: Cerebrovascular and inflamm-ageing link to neurodegeneration and dementia
Funder: Medical Research Council

Abstract: Many neurological disorders including small vessel disease (SVD) and Alzheimer’s disease (AD) are associated with blood-brain barrier (BBB) dysfunctions. Early degeneration of brain pericytes and activation of endothelial cells are thought to be critical factors in the development and progression of common dementias. However, the molecular pathways which drive endothelial cell and pericyte dysfunctions are largely unknown, with no established therapies. The overarching aim of my research programme is to identify key mechanisms and pathways that lead to impaired endothelium-pericyte crosstalk which is detrimental not only for proper BBB functions, but also to subsequent neuronal and cognitive functions. We will focus on what can cause pericytes to become dysfunctional and ultimately die, and how pericyte loss in turn destabilizes the endothelial cells lining the BBB. In parallel, we will investigate the downstream impact of vascular dysfunctions on the brain’s immune response. We will specifically assess how both brain-resident perivascular microglia and infiltrated immune cells can either promote or disrupt BBB integrity. Greater knowledge in these areas may lead to novel therapeutic targets for cerebrovascular protection in chronic neurodegenerative diseases, particularly SVD and AD In my UK DRI research programme, we aim to address these questions by using innovative genetic mouse models and combining cutting-edge live imaging technologies (i.e., magnetic resonance imaging, positron emission tomography, and two-photon microscopy) with analysis of evolving endothelial cell, pericyte, and immune cell transcriptional signatures at single-cell resolution. We hypothesise that endothelial activation at the BBB is an early trigger for pericyte dysfunction and intends to better understand the consequences of this to the BBB as a whole. Specifically, we will: 1. Assess the impact of modulating both pericyte and endothelial cell functions to define the downstream consequences for the other cell type, and for BBB functions. 2. Determine the role of resident microglia and systemic immune cells in responding to a compromised endothelium-pericyte interplay, and their contribution to BBB integrity. 3. Test BBB preserving interventions in an in vitro platform. 4. Define the impact of vascular-targeted therapeutic interventions for ameliorating vascular, neuronal, and cognitive functions in the context of SVD and AD. This programme has broader relevance to human SVD and AD where pericytes were shown to die early. The identification of modifiable pathways which contribute to vascular dysfunctions is a major focus of global efforts to tackle the vascular contribution to dementia. The outcome of this proposal will shine light on the cellular and molecular underpinnings of vascular dysfunctions leading to pericyte death and will help designing vascular-targeted treatment strategies to protect the brain in SVD and AD, and possibly other neurological disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL