Altered microglia states and microglia-endothelial cell axis in relation to white matter disease progression in VCID

项目总结 脑白质异常可预测血管性认知障碍和痴呆的发展 (VCID)。血管机制，包括脑低灌注、脑白质异常。 然而，导致白质功能障碍和认知功能障碍的机制仍然很差。 了解限制了有效治疗方法的发展。利用人类死后组织和研究 在动物模型中，我们已经表明，损害白质的关键机制包括破坏脑白质 小胶质细胞稳态、内皮细胞功能障碍、血脑屏障破坏与慢性 轻度微血管炎症。我们的研究现在提供了令人信服的支持，即小胶质细胞的状态 (丰度/功能)通过与内皮细胞的相互作用影响白质异常。我们的新兴数据也 显示小胶质细胞状态对空间依赖的微血管脑血流量(CBF)减少的反应 举止。白质和灰质-小胶质细胞的体积分析暗示白质小胶质细胞的敏感性 需要更深入地调查与舱室相关的多样性。此外，我们的新数据表明 小胶质细胞可能是微血管张力和血流动力学的重要调节细胞。我们将在这项工作的基础上继续努力 检验小胶质细胞状态特异性调节剂影响小胶质细胞-微血管内皮细胞的假说 脑内稳态与WM异常及认知功能障碍的发生发展 VCID。我们的跨学科团队(爱丁堡、纽卡斯尔、苏塞克斯(英国))在神经免疫方面拥有专业知识 机制、髓鞘和血管生物学将架起动物模型与患者之间的桥梁。我们将使用专业的 空间转录方法，成像模式和计算方法，以提供 全面了解小胶质细胞的多样性及其对微血管和白质改变的影响 在VCID中。将实现以下主要目标： 目的1：鉴定小胶质细胞-微血管内皮细胞异质性及其与细胞间通讯的关系 人类VCID中的WM异常 目的2：确定特定的小胶质细胞状态调节剂是否能改善小胶质细胞-微血管内皮细胞 VCID模型中的动态平衡和预防西医疾病进展 目的3：实时了解小胶质细胞与微血管的相互作用。 VCID模型中的西医疾病进展。 这些研究将为确定小胶质细胞状态如何影响小胶质细胞-EC交叉提供关键基础 VCID患者的谈话和白质完整性，也与阿尔茨海默病有关。我们的目标是识别小说 早期治疗干预以减轻认知功能衰退的免疫调节靶点。

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.