The contribution of perivascular macrophages to cerebral microvascular dysfunction in Alzheimer's

项目总结 肥胖、炎症和脑微血管功能障碍是高度相互依赖的危险因素 阿尔茨海默氏症。然而，对这些风险因素如何相互作用的机械性理解 阿尔茨海默氏症的进展是有限的。这一缺口将通过目前的行政补编加以解决。 来自申请人实验室的初步数据和发表的研究表明，在大脑之外，巨噬细胞 是导致肥胖症患者微血管功能障碍的主要炎症介质。有趣的是， 巨噬细胞也存在于大脑中，它们定位于周围的血管周围空间。 脑微血管的穿透小动脉，尽管它们对血管功能和 阿尔茨海默氏症的进展情况并不明确。目前的目标是评估血管周围巨噬细胞如何 参与了肥胖和阿尔茨海默氏症之间的相互作用。这一目标将通过测试来实现 肥胖依赖型炎症促进阿尔茨海默病进展的中心假说 通过增加脑微血管功能障碍导致的疾病。提出了两个具体目标：目标1将界定 肥胖和炎症如何导致阿尔茨海默病患者的脑微血管功能障碍 目标2将定义血管周围巨噬细胞如何参与阿尔茨海默病的病理。饮食诱导 肥胖将在阿尔茨海默氏症转基因小鼠模型中进行研究。 对雄性和雌性动物的炎症和脑微血管系统进行评估 巨噬细胞表型分析、巨噬细胞耗竭研究、活体深部脑成像显微镜以及 新鲜分离的穿透小动脉段的体外功能分析。完成这些目标将解决 为什么肥胖是阿尔茨海默病的危险因素的问题，通过建立一种新的机制来实现 炎症通过巨噬细胞依赖的脑微血管功能障碍加重阿尔茨海默病。

PROJECT SUMMARY Obesity, inflammation and cerebral microvascular dysfunction are highly interdependent risk factors for Alzheimer’s disease. However, the mechanistic understanding of how these risk factors interact to influence the progression of Alzheimer’s is limited. This gap will be addressed by the current administrative supplement. Preliminary data and published studies from the applicant’s lab show that outside of the brain, macrophages are the dominant inflammatory mediator driving microvascular dysfunction in obesity. Intriguingly, macrophages are also present within the brain, where they are localized to the perivascular space surrounding the penetrating arterioles of the cerebral microvasculature, although their contribution to vascular function and Alzheimer’s progression is poorly defined. The current objective is to assess how perivascular macrophages are involved in the interaction between obesity and Alzheimer’s. The objective will be accomplished by testing the central hypothesis that obesity-dependent inflammation contributes to the progression of Alzheimer’s disease by increasing cerebral microvascular dysfunction. Two specific aims are proposed: aim 1 will define how obesity and inflammation contribute to cerebral microvascular dysfunction in Alzheimer’s Disease, and aim 2 will define how perivascular macrophages contribute to Alzheimer’s Disease pathology. Diet-induced obesity will be studied in a transgenic mouse model of Alzheimer’s. The interaction between obesity, inflammation and the cerebral microvasculature will be assessed in both male and female animals using macrophage phenotype analysis, macrophage depletion studies, in vivo deep brain imaging microscopy, and in vitro functional assays of freshly isolated penetrating arteriolar segments. Completing these aims will address the question of why obesity is a risk factor for Alzheimer’s disease by establishing a new mechanism in which inflammation exacerbates Alzheimer’s through macrophage-dependent cerebral microvascular dysfunction.