Altered Microglia States and Microglia-Endothelial Cell Axis in Relation to White Matter Disease Progression in VCID

PROJECT SUMMARY Cerebral white matter abnormalities predict the development of vascular cognitive impairment and dementia (VCID). Vascular mechanisms, including cerebral hypoperfusion, underly white matter abnormalities. However, the mechanisms leading to white matter dysfunction and cognitive performance remain poorly understood limiting the development of effective treatments. Using human post-mortem tissues and studies in animal models, we have shown that key mechanisms that damage white matter include disruption of microglia homeostasis, endothelial cell (EC) dysfunction, blood brain barrier (BBB) breakdown and chronic low-grade microvascular inflammation. Our studies now provide compelling support that microglia ‘state’ (abundance/function) influence white matter abnormalities via interactions with ECs. Our emerging data also show microglia states respond to reduced microvascular cerebral blood flow (CBF) in a spatially-dependent manner. Bulk analysis of white matter and grey matter-microglia implicates white matter microglial sensitivity warranting more in-depth investigation of compartment-related diversity. Further our novel data indicate microglia may be critical regulators of microvascular tone and hemodynamics. We will build on this work to test the hypothesis that specific regulators of microglia state influence microglia-microvascular EC homeostasis and the development and progression of WM abnormalities and cognitive deficits in VCID. Our cross-disciplinary team (Edinburgh, Newcastle, Sussex (UK)) with expertise in neuroimmune mechanisms, myelin and vascular biology will bridge animal model to patient. We will use specialised spatial transcriptomic approaches, imaging modalities and computational approaches to provide a comprehensive insight to the microglial diversity and how it affects microvascular and white matter alterations in VCID. The following key aims would be undertaken: Aim 1: To identify microglia-microvascular EC heterogeneity and intercellular communication in relation to WM abnormalities in human VCID Aim 2: To determine if specific regulators of microglia state can improve microglia -microvascular EC homeostasis and prevent WM disease progression in a model of VCID Aim 3: To provide functional insight to microglia-microvascular interactions, in real time, in relation to WM disease progression in a model of VCID. These studies will provide a critical foundation to define how microglia state influences microglia-EC cross talk and white matter integrity in VCID, also of relevance to Alzheimer’s disease. The goal is to identify novel immunomodulatory targets for early therapeutic intervention to attenuate cognitive decline.